Breast Cancer

BREAST CANCER

Synopsis:

Background
Risk Factors
Nutrients & Rationale
Diet
Suggested Supplementation

 

BACKGROUND

Breast cancer occurs when cells in the breast tissue divide and grow without control. The cell cycle is the natural mechanism that regulates the growth and death of cells. When the normal cell regulators malfunction and cells do not die at the proper rate, there is a failure of cell death (apoptosis) therefore cell growth goes unchecked. As a result, cancer begins to develop as cells divide without control, accumulating into a mass of extra tissue called a tumor. A tumor can be either non-cancerous (benign) or cancerous (malignant). As a tumor grows, it elicits new blood vessel growth from the surrounding normal healthy tissues and diverts blood supply and nutrients away from this tissue to feed itself. This process is termed “angiogenesis”- the development (genesis) of new blood vessels (angio). Unregulated tumor angiogenesis facilitates the growth of cancer throughout the body.

Cancer cells have the ability to leave the original tumor site, travel to distant locations, and recolonize. This process is called metastasis and it occurs in organs such as the liver, lungs, and bones. Both the bloodstream and lymphatic system (the network connecting lymph nodes throughout the body) serve as ideal vehicles for the traveling cancer. Although, these traveling cancer cells do not always survive beyond the tumor, if they do survive, the cancer cells will again begin to divide abnormally and will create tumors in each new location. A person with untreated or treatment-resistant cancer may eventually die of the disease if vital organs such as the liver or lungs are invaded, overtaken, and destroyed.

Cancerous tumors in the breast usually grow slowly. It is thought that by the time a tumor is large enough to be felt as a lump, it may have been growing for as long as 10 years. This has led to the belief that undetectable spread of tumor cells (micrometastasis) may have already occurred by the time of the diagnosis. Therefore, preventive measures such as a healthy balanced diet and lifestyle, nutritional supplementation, and exercise are of primary importance against the development of cancer. Early diagnosis is the best way to reduce the risk of dying from breast cancer. This can be accomplished by monthly self-breast exams, annual clinical breast exams and screening mammography. If breast cancer is detected, a multimodality approach incorporating nutritional supplementation, dietary modification, detoxification, and one or more of the following may be considered: surgery, chemotherapy, radiation, hormone therapy, or vaccine therapy.

A wide variety of factors may influence an individual's likelihood of developing breast cancer. The risk factors for breast cancer include: female gender, age, previous breast cancer, benign breast disease, hereditary factors (family history of breast cancer), early age at menarche (first menstrual period), late age at menopause, late age at first full-term pregnancy, obesity, low physical activity, use of postmenopausal hormone replacement therapy, use of oral contraceptives, exposure to low-dose ionizing radiation in midlife and exposure to high-dose ionizing radiation early in life.

Correlated risk factors for breast cancer include never having been pregnant, having only one pregnancy rather than many, not breast feeding after pregnancy, diethylstilbestrol (DES), certain dietary practices (high intake of fat and low intakes of fiber, fruits, and vegetables), tobacco, smoking, breast trauma, large breast size, synthetic estrogens, electromagnetic fields, and alcohol consumption. Alcohol is known to increase estrogen levels. Alcohol use appears to be more strongly associated with risk of lobular carcinomas and hormone receptor-positive tumors than it is with other types of breast cancer (Li et al. 2003).

A novel growth inhibitor recently identified as estrogen down-regulated gene 1 (EDG1) was found to be switched off (down-regulated) by estrogens. Inhibiting EDG1 expression in breast cells resulted in increased breast cell growth, whereas over-expression of EDG1 protein in breast cells resulted in decreased cell growth and decreased anchorage-independent growth, supporting the role of EDG1 in breast cancer (Wittmann et al. 2003).

 

 

Indole-3-Carbinol (I3C)

There are different forms of estrogen in the body, and the stronger estrogen can contribute to breast cancer development.  Estriol is considered to be a more desirable form of estrogen. It is less active than estradiol, the stronger form of estrogen, so when it occupies the estrogen receptor, it blocks estradiol's strong "growth" signals. Indole-3-carbinol (I3C) can convert estradiol (the stronger form) into the weaker form, estriol. Using I3C, the conversion of estradiol to estriol was increased by 50% in 12 healthy people (Michnovicz et al. 1991). Furthermore, in female mice prone to developing breast cancer, I3C reduced the incidence of cancer and the number of tumors significantly.

Indole-3-carbinol (I3C) is a phytochemical isolated from cruciferous vegetables (broccoli, cauliflower, Brussels sprouts, turnips, kale, green cabbage, mustard seed, etc.). I3C given to 17 men and women for 2 months reduced the levels of strong estrogen, and increased the levels of weak estrogen. But more importantly, the level of an estrogen metabolite associated with breast and endometrial cancer, 16--a-hydroxyestrone, was reduced by I3C (Bradlow et al. 1991).

When I3C changes "strong" estrogen to "weak" estrogen, the growth of human cancer cells is inhibited by 54-61% (Telang et al. 1997). Moreover, I3C provoked cancer cells to self-destruct (kill themselves via apoptosis). Induction of cell death is an approach to suppress carcinogenesis and is the prime goal of cytotoxic chemotherapy. The increase in apoptosis induced by I3C before initiation of new tumor development may contribute to suppression of tumor progression. Thus, this phytonutrient may become a standard adjunct in the treatment of breast cancer (Zhang et al. 2003).

I3C inhibits human breast cancer cells (MCF7) from growing by as much as 90% in culture; growth arrest does not depend on estrogen receptors (Cover et al. 1998). Furthermore, I3C induces apoptosis in tumorigenic (cancerous) but not in nontumorigenic (non-cancerous) breast epithelial cells (Rahman et al. 2003).

16-a-Hydroxyestrone (16-OHE) and 2-hydroxyestrone (2-OHE) are metabolites of estrogen in addition to estriol and estradiol. 2-OHE is biologically inactive, while 16-OHE is biologically active; that is, like estradiol, it can send "growth" signals. In breast cancer, the dangerous 16-OHE is often elevated, while the protective 2-OHE is decreased. Cancer-causing chemicals change the metabolism of estrogen so that 16-OHE is elevated. Studies show that people who take I3C have beneficial increases in the "weak" estriol form of estrogen and also increases in protective 2-OHE.

African-American women who consumed I3C, 400 mg for 5 days, experienced an increase in the "good" 2-OHE and a decrease of the "bad" 16-OHE. However, it was found that the minority of women who did not demonstrate an increase in 2-OHE, had a mutation in a gene that helps metabolize estrogen to the 2-OHE version. Those women had an eight times higher risk of breast cancer (Telang et al. 1997).

I3C Stops Cancer Cells from Growing

Tamoxifen is a drug prescribed to reduce breast cancer metastases and improve survival. I3C has modes of action similar to tamoxifen. I3C inhibited the growth of estrogen-receptor-positive breast cancer cells by 90% compared to 60% for tamoxifen. The mode of action attributed to I3C's impressive effect was interfering with the cancer cell growth cycle. Adding tamoxifen to I3C gave a 5% boost (95% total inhibition) (Cover et al. 1999).

In estrogen-receptor-negative cells, I3C stopped the synthesis of DNA by about 50%, whereas tamoxifen had no significant effect. I3C also restored p21 and other proteins that act as checkpoints during the synthesis of a new cell. Tamoxifen showed no effect on p21. Restoration of these growth regulators is extremely important. For example, tumor suppressor p53 works through p21 that I3C restores. I3C also inhibits cancers caused by chemicals. If animals are fed I3C before exposure to cancer-causing chemicals, DNA damage and cancer are virtually eliminated (Cover et al. 1999).

A study on rodents shows that damaged DNA in breast cells is reduced 91% by I3C. Similar results are seen in the liver (Devanaboyina et al. 1997). Female smokers taking 400 mg of I3C significantly reduced their levels of a major lung carcinogen. Cigarette chemicals are known to adversely affect estrogen metabolism (Taioli et al. 1997).

There is no proven way to prevent breast cancer, but the best and most comprehensive scientific evidence so far supports phytochemicals such as I3C (Meng et al. 2000). The results from a placebo-controlled, double-blind dose-ranging chemoprevention study on 60 women at increased risk for breast cancer demonstrated that I3C at a minimum effective dosage 300 mg per day is a promising agent for breast cancer prevention (Wong et al. 1997). The results of a single-blind phase I trial which studied the effectiveness of I3C in preventing breast cancer in nonsmoking women who are at high risk of breast cancer are awaited. The rationale for this study is that I3C, ingested twice daily, may be effective at preventing breast cancer.

I3C was found to be superior to 80 other compounds, including tamoxifen, for anticancer potential. Indoles, which down-regulate estrogen receptors, have been proposed as promising agents in the treatment and prevention of cancer and autoimmune diseases such as multiple sclerosis, arthritis, and lupus. Replacement of all the chemically altered estrogen drugs, such as tamoxifen, with a new generation of chemically altered indole drugs that fit in the aryl-hydrocarbon (Ah) receptor and regulate estrogen indirectly may prove beneficial to cancer patients (Bitonti et al. 1999). An I3C tetrameric derivative (chemically derived) is currently a novel lead inhibitor of breast cancer cell growth, considered a new, promising therapeutic agent for both ER+ and ER- breast cancer (Brandi et al. 2003).

A summary of studies shows that indole-3-carbinol (I3C) can:

• Increase the conversion of estradiol to the safer estriol by 50% in healthy people in just 1 week (Michnovicz et al. 1991)
• Prevent the formation of the estrogen metabolite, 16,alpha-hydroxyestrone, that prompts breast cancer cells to grow (Chen et al. 1996), in both men and women in 2 months (Michnovicz et al. 1997)
• Stop human cancer cells from growing (54-61%) and provoke the cells to self-destruct (apoptosis) (Telang et al. 1997)
• Inhibit human breast cancer cells (MCF7) from growing by as much as 90% in vitro (Ricci et al. 1999)
• Inhibit the growth of estrogen-receptor-positive breast cancer cells by 90%, compared to tamoxifen's 60%, by stopping the cell cycle (Cover et al. 1999)
• Prevent chemically induced breast cancer in rodents by 70-96%. Prevent other types of cancer, including aflatoxin-induced liver cancer, leukemia, and colon cancer (Grubbs et al. 1995)
• Inhibit free radicals, particularly those that cause the oxidation of fat (Shertzer et al. 1988)
• Stop the synthesis of DNA by about 50% in estrogen-receptor-negative cells, whereas tamoxifen had no significant effect (Cover et al. 1998)
• Restore p21 and other proteins that act as checkpoints during the synthesis of a new cancer cell. Tamoxifen has no effect on p21 (Cover et al. 1998)
• Virtually eliminate DNA damage and cancer prior to exposure to cancer-causing chemicals (in animals fed I3C) (Grubbs et al. 1995)
• Reduce DNA damage in breast cells by 91% (Devanaboyina et al. 1997)
• Reduce levels of a major nitrosamine carcinogen in female smokers (Taioli et al. 1997)

Suggested dosage: Take one 200-mg capsule of I3C twice a day, for those under 120 pounds. For those who weigh more than 120 pounds, three 200-mg capsules a day are suggested. Women who weigh over 180 pounds should take four 200-mg I3C capsules a day.

Caution: Pregnant women should not take I3C because of its modulation of estrogen.

 

Apigenin

Apigenin, a flavone (ie, a class of flavonoids) that is present in fruits and vegetables (eg, onions, oranges, tea, celery, artichoke, and parsley), has been shown to possess anti-inflammatory, antioxidant, and anticancer properties. Many studies have confirmed the cancer chemopreventive effects of apigenin (Patel 2007).

Apigenin stimulates apoptosis in breast cancer cells (Chen 2007). A 2012 study showed that apigenin slowed the progression of human breast cancer by inducing cell death, inhibiting cell proliferation, and reducing expression of a gene associated with cancer growth (Her2/neu). In another study, it was noted that blood vessels responsible for feeding cancer cells were smaller in apigenin-treated mice compared to untreated mice. This is significant because smaller vessels mean restricted nutrient flow to the tumors and may have served to starve the cancer as well as limit its ability to spread (Mafuvadze 2012).

Apigenin has been proven to have a synergistic treatment effect when combined with the chemotherapy drug paclitaxel (Xu 2011). In a study, apigenin increased the efficacy of the chemotherapy drug 5-Fluorouracil against breast cancer cells (Choi 2009).

 

Astragalus

Astragalus, an herb used for centuries in Asia, has exhibited immune-stimulatory effects. Astragalus potentiates lymphokine-activated killer cells (Chu 1988). One study found that astragalus could partially restore depressed immune function in tumor-bearing mice (Cho 2007a), while another concluded that “…astragalus could exhibit anti-tumor effects, which might be achieved through activating the…anti-tumor immune mechanism of the host” (Cho 2007b).

It was observed in a clinical trial that astragalus inhibited the proliferation of breast cancer cells. Authors of the study stated, “The antiproliferation mechanisms may be related to its effects of up-regulating the expressions of p53…” (Ye 2011). Similar findings were noted in a previous experiment (Deng 2009).

 

Blueberry

Blueberries are rich in anthocyanins (ie, dark pigments in fruits) and pterostilbenes (ie, antioxidant closely related to resveratrol). The anti-cancer effects of blueberries are mediated by multiple mechanisms:

• Blueberry extracts block DNA damage. Damage to cellular DNA underlies most forms of cancer. By preventing such damage, blueberry extracts can block the malignant transformation of healthy cells (Aiyer 2008).
• Blueberry extracts inhibit angiogenesis. Rapidly-growing cancers recruit new blood vessels to meet their ravenous appetites for nutrients and oxygen. Blueberry inhibits new tumor blood vessel growth, known as angiogenesis (Gordillo 2009; Liu 2011).
• Blueberry extracts trigger cancer cells’ suicide. If normal cells replicate too fast, they are programmed to die through apoptosis. Cancerous cells, by contrast, ignore that programming, constantly doubling their population unchecked. Blueberry components restore normal programming and induce apoptosis in cells from a variety of cancers, putting the brakes on their rapid growth (Katsube 2003; Yi 2005; Seeram 2006; Srivastava 2007; Alosi 2010).
• Blueberry extracts stop excessive proliferation. Uncontrolled cell reproduction results in formation of dangerous tumors, as cells ignore the normal signals to stop growing. By restoring normal cellular signaling, blueberry extracts stop such out-of-control proliferation (Yi 2005; Adams 2010; Nguyen 2010). In an experimental breast cancer cell line, blueberry significantly reduced breast cancer cell proliferation, leading the researchers to state that “blueberry anthocyanins … demonstrated anticancer properties by inhibiting cancer cell proliferation and by acting as cell antiinvasive factors and chemoinhibitors” (Faria 2010).
• Blueberry extracts slow tumor spread by invasion and metastasis. Solid cancers produce matrix metalloproteinases, which are “protein-melting” enzymes that help them invade adjacent tissues and that enable them to metastasize. Blueberry extracts block matrix metalloproteinases, thereby inhibiting cancer invasion and metastasis (Adams 2010a; Matchett 2005). In one experiment published in 2011, blueberry extract was administered to mice with breast cancer. Compared to the control group, tumor volume was 75% lower in mice fed blueberry extract. Moreover, mice fed blueberry extract developed 70% fewer liver metastases and 25% fewer lymph node metastases compared to the control group (Adams 2011).

 

Chrysin

Breast cancers that are estrogen-receptor positive can grow and be exacerbated in the presence of estrogen in the body. One aim of drug therapy for estrogen-receptor positive breast cancer is to decrease the levels of estrogen in the body. To that end, drugs used to block the enzyme (ie, aromatase) that converts testosterone into estrogen (ie, aromatase inhibitors) are widely used in women with estrogen-receptor positive breast cancer. Chrysin, a flavonoid, is a natural aromatase inhibitor (Campbell 1993; Mohammed 2011).

 

Coffee

Coffee, especially brews enriched with chlorogenic acid, protect cells against the DNA damage that leads to aging and cancer development (Bakuradze 2011; Hoelzl 2010; Misik 2010). Growing tumors develop the ability to invade local and regional tissue by increasing their production of “protein-melting” enzymes called matrix metalloproteinases. Chlorogenic acid—present in coffee—strongly inhibited matrix metalloproteinase activity (Jin 2005; Belkaid 2006).

A 2011 study reported that postmenopausal women who drank 5 cups of coffee dailyexhibited a 57% decreased risk of developing estrogen-receptor negative (non-hormone-responsive) breast cancer (Li 2011). Chlorogenic acid and other polyphenols are the likely beneficial agents in such cancers (Bageman 2008).

 

Curcumin

Curcumin is extracted from the spice turmeric and is responsible for the orange/yellow pigment that gives the spice its unique color. Turmeric is a perennial herb of the ginger family and a major component of curry powder. Chinese and Indian people, both in herbal medicine and in food preparation, have safely used it for centuries.

Curcumin has a number of biological effects in the body. However, one of the most important functions is curcumin's ability to inhibit growth signals emitted by tumor cells that elicit angiogenesis (growth and development of new blood vessels into the tumor).

Curcumin inhibits the epidermal growth factor receptor and is up to 90% effective in a dose-dependent manner. It is important to note that while curcumin has been shown to be up to 90% effective in inhibiting the expression of the epidermal growth factor receptor on cancer cell membranes, this does not mean it will be effective in 90% of cancer patients or reduce tumor volume by 90%. However, because two-thirds of all cancers overexpress the epidermal growth factor receptor and such overexpression frequently fuels the metastatic spread of the cancer throughout the body, suppression of this receptor is desirable.

Other anticancer mechanisms of curcumin include:

• Inhibition of the induction of basic fibroblast growth factor (bFGF). bFGF is both a potent growth signal (mitogen) for many cancers and an important signaling factor in angiogenesis (Arbiser et al. 1998).
• Antioxidant activity. In vitro it has been shown to be stronger than vitamin E in prevention of lipid peroxidation (Sharma 1976; Toda et al. 1985).
• Inhibition of the expression of COX-2 (cyclooxygenase 2), the enzyme involved in the production of prostaglandin E2 (PGE-2), a tumor-promoting hormone-like agent (Zhang et al. 1999).
• Inhibition of a transcription factor in cancer cells known as nuclear factor-kappa B (NF-KB). Many cancers overexpress NF-KB and use this as a growth vehicle to escape regulatory control (Bierhaus et al. 1997; Plummer et al. 1999).
• Increased expression of nuclear p53 protein in human basal cell carcinomas, hepatomas, and leukemia cell lines. This increases apoptosis (cell death) (Jee et al. 1998).
• Increases production of transforming growth factor-beta (TGF-beta), a potent growth inhibitor, producing apoptosis (Park et al. 2003; Sporn et al. 1989).
• TGF-beta is known to enhance wound healing and may play an important role in the enhancement of wound healing by curcumin (Mani H et al. 2002; Sidhu et al. 1998).
• Inhibits PTK (protein tyrosine kinases) and PKC (protein kinase C). PTK and PKC both help relay chemical signals through the cell. Abnormally high levels of these substances are often required for cancer cell signal transduction messages. These include proliferation, cell migration, metastasis, angiogenesis, avoidance of apoptosis, and differentiation (Reddy et al. 1994; Davidson et al. 1996).
• Inhibits AP-1 (activator protein-1) through a non-antioxidant pathway. While curcumin is an antioxidant (Kuo et al. 1996), it appears to inhibit signal-transduction via protein phosphorylation thereby decreasing cancer-cell activity, regulation, and proliferation (Huang et al. 1991).

Based on the favorable, multiple mechanisms listed above, higher-dose curcumin would appear to be useful for cancer patients to take. However, as far as curcumin being taken at the same time as chemotherapy drugs, there are contradictions in the scientific literature. Therefore, caution is advised.

Curcumin's effects are a dose dependent response, and a standardized product is essential. The recommended dose is four 900-mg capsules 3 times per day, preferably with food.

 

Green Tea

As a tumor grows it elicits new capillary growth (angiogenesis) from the surrounding normal tissues and diverts blood supply and nutrients away from the tissue to feed itself. Unregulated tumor angiogenesis can facilitate the growth of cancer throughout the body. Anti-angiogenesis agents, including green tea, inhibit this new tumor blood vessel (capillary) growth.

Green tea contains epigallocatechin gallate EGCG, a polyphenol that helps to block the induction of vascular endothelial growth factor (VEGF). Scientists consider VEGF essential in the process of angiogenesis and tumor endothelial cell survival. It is the EGCG fraction of green tea that makes it a potentially effective adjunct therapy in the treatment of breast cancer. In vivo studies have shown green tea extracts to have the following actions on human cancer cells (Jung et al. 2001b; Muraoka et al. 2002):

• Inhibition of tumor growth by 58%
• Inhibition of activation of nuclear factor-kappa beta
• Inhibition of microvessel density by 30%
• Inhibition of tumor-cell proliferation in vitro by 27%
• Increased tumor-cell apoptosis 1.9-fold
• Increased tumor endothelial-cell apoptosis threefold

The most current research shows that green tea may have a beneficial effect in treating cancer. While drinking green tea is a well-documented method of preventing cancer, it is difficult for the cancer patient to obtain a sufficient quantity of EGCG anticancer components in that form. Standardized green tea extract is more useful then green tea itself because the dose of EGCG can be precisely monitored and greater doses can be ingested without excessive intake of liquids. A suggested dose for a person with breast cancer is 5 capsules of 350-mg lightly caffeinated green tea extract 3 times a day with each meal. Each capsule should provide at least 100 mg of EGCG. It may be desirable to take a decaffeinated version of green tea extract in the evening to ensure that the caffeine does not interfere with sleep. Those sensitive to caffeine may also use this decaffeinated form.

However, there are benefits to obtaining some caffeine. Studies show that caffeine potentiates the anticancer effects of tea polyphenols, including the critical EGCG. Caffeine will be discussed in further detail later in this protocol. Green tea extract is available in a decaffeinated form for those sensitive to caffeine or those who want to take the less-stimulating decaffeinated green tea extract capsules for their evening dose.

 

Conjugated Linoleic Acid (CLA)

Conjugated linoleic acid (CLA) found naturally, as a component of beef and milk, refers to isomers of octadecadienoic acid with conjugated double bonds. CLA is essential for the transport of dietary fat into cells, where it is used to build muscle and produce energy. CLA is incorporated into the neutral lipids of mammary fat (adipocyte) cells, where it serves as a local reservoir of CLA. It has been proposed that CLA may be an excellent candidate for prevention of breast cancer (Ip et al. 2003). Low levels of CLA are found in breast cancer patients but these do not influence survival. Nevertheless, it has been hypothesized that a higher intake of CLA might have a protective effect on the risk of metastasis (Chajes et al. 2003).

CLA was shown to prevent mammary cancer in rats if given before the onset of puberty. CLA ingested during the time of the "promotion" phase of cancer development conferred substantial protection from further development of breast cancer in the rats by inducing cell kill of pre-cancerous lesions (Ip et al. 1999b). It was determined that feeding CLA to female rats while they were young and still developing conferred life-long protection against breast cancer. This preventative action was achieved by adding enough CLA to equal 0.8% of the animal's total diet (Ip et al. 1999a).

CLA inhibits the proliferation of human breast cancer cells (MCF-7), induced by estradiol and insulin (but not EGF). In fact, CLA caused cell kill (cytotoxicity) when tumor cells were induced with insulin (Chujo et al. 2003). The antiproliferative effects of CLA are partly due to their ability to elicit a p53 response that leads to growth arrest (Kemp et al. 2003). CLA elicits cell killing effects in human breast tumor cells through both p53-dependent and p53 independent pathways according to the cell type (Majumder et al. 2002). Refer to Cancer Treatment The Critical Factors, for more information on determining the p53 status of cancer. The effects of CLA are mediated by both direct action (on the epithelium) as well as indirect action through the stroma.

The growth suppressing effect of CLA may be partly due to changes in arachidonic distribution among cellular lipids and an altered prostaglandin profile (Miller et al. 2001). Intracellular lipids may become more susceptible to oxidative stress to the point of producing a cytotoxic effect (Devery et al. 2001). CLA has the ability to suppress arachidonic acid. Since arachidonic acid can produce inflammatory compounds that can promote cancer proliferation, this may be yet another explanation for CLA's anticancer effects.

Recommendation for CLA is a dose of 3000-4000 mg daily, which is approximately 1% of the average human diet. The suggested amount required to obtain the overall cancer-preventing effects is only 3000-4000 mg daily in divided doses.

CLA may work via a mechanism similar to that of antidiabetic drugs not only by enhancing insulin-sensitivity but also by increasing plasma adiponectin levels, alleviating hyperinsulinemia (Nagao et al. 2003) protecting against cancer. A number of human cancer cell lines express the PPAR-gamma transcription factor, and agonists for PPAR-gamma can promote apoptosis in these cell lines and impede their clonal expansion both in vitro and in vivo. CLA can activate PPAR-gamma in rat adipocytes, possibly explaining CLA's antidiabetic effects in Zucker fatty rats. A portion of CLA's broad-spectrum anticarcinogenic activity is probably mediated by PPARgamma activation in susceptible tumor (McCarty 2000). However, CLA’s anticarcinogenic effects could not be confirmed in one epidemiologic study in humans (Voorips et al. 2002). (Note: The term PPAR-gamma is an acronym for peroxisome proliferator-activatedreceptor-gamma. A PPAR-gamma agonist such as Avandia®, Actos®, or CLA activates the PPAR-gamma receptor. This class of drug is being investigated as a potential adjuvant therapy against certain types of cancer.)

 

Caffeine

Caffeine occurs naturally in green tea and has been shown to potentiate the anticancer effects of tea polyphenols. Caffeine is a model radio-sensitizing agent that is thought to work by abolishing the radiation-induced G2-phase checkpoint in the cell cycle. Caffeine can induce apoptosis of a human lung carcinoma cell line by itself and it can act synergistically with radiation to induce tumor cell kill and cell growth arrest. The cancer cell killing effect of caffeine is dependent on the dose (Qi et al. 2002).

Caffeine enhances the tumor cell killing effects of anticancer drugs and radiation. A preliminary report on radiochemotherapy combined with caffeine for high-grade soft tissue sarcomas in 17 patients, (treated with cisplatin, caffeine, and doxorubicin after radiation therapy) determined complete response in six patients, partial response in six and no change in five patients. The effectiveness rate of caffeine-potentiated radiochemotherapy was therefore 17%, and contributed to a satisfactory local response and the success of function-saving surgery for high-grade soft tissue sarcomas (Tsuchiya et al. 2000).

In a randomized, double blind placebo-controlled crossover study, the effects of caffeine as an adjuvant to morphine in advanced cancer patients was found to benefit the cognitive performance and reduce pain intensity (Mercadante et al. 2001).

To ascertain the inhibitory effects of caffeine, mice at high risk of developing malignant and nonmalignant tumors (SKH-1), received oral caffeine as their sole source of drinking fluid for 18-23 weeks. Results revealed that caffeine inhibited the formation and decreased the size of both nonmalignant tumors and malignant tumors (Lou et al. 1999).

In cancer cells, p53 gene mutations are the most common alterations observed (50-60%) and are a factor in both carcinomas and sarcomas. Caffeine has been shown to potentiate the destruction of p53-defective cells by inhibiting p53's growth signal. The effects of this are to inhibit and override the DNA damage-checkpoint and thus kill dividing cells. Caffeine uncouples cell-cycle progression by interfering with the replication and repair of DNA(Sakurai et al. 1999; Ribeiro et al. 1999; Jiang et al. 2000; Valenzuela et al. 2000).

Caffeine inhibits the development of Ehrlich ascites carcinoma in female mice (Mukhopadhyay 2001). Topical application of caffeine inhibits the occurrence of cancer and increases tumor cell death in radiation-induced skin tumors in mice (Lu et al. 2002). Caffeine inhibits solid tumor development and lung experimental metastasis induced by melanoma cells (Gude et al. 2001).

Consumption of coffee, tea, and caffeine was not associated with breast cancer incidence in a study of 59,036 Swedish women (aged 40-76 years) (Michels et al. 2002).

 

Lignans

Lignans are found in high concentrations in flaxseed and sesame. Once consumed, lignans are converted in the intestines into enterolactone. Enterolactone has been shown to inhibit angiogenesis and promote cancer cell apoptosis (Bergman 2007; Chen 2007).

Enterolactone inhibits the aromatase enzyme, which converts testosterone into estrogen (Brooks 2005; Wang 1994).

Researchers conducted an analysis of breast cancer risk and dietary lignan intake in 3158 women. They determined that premenopausal women with the highest lignan intake had a 44% reduced risk of developing breast cancer (McCann 2004).

Thirty-two women awaiting surgery for breast cancer were randomized to receive either a muffin containing 25 grams of flaxseeds or no flaxseed (control group). Post-operative analysis of the cancerous tissue revealed that markers of tumor growth were reduced by 30-71% in the flaxseed group versus no reduction in the control group (Thompson 2005). Scientists concluded that “dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer.”

In order to examine the relationship between dietary lignan intake and breast cancer, researchers assessed the diets of 1122 women in the 1-2 years before breast cancer diagnosis. They noted that postmenopausal women with the highest dietary intake of lignans had a 71% decreased risk of death from breast cancer (McCann 2010).

 

Melatonin

One of the most important supplements for a breast cancer patient is the hormone melatonin. Melatonin inhibits human breast cancer cell growth (Cos et al. 2000) and reduces tumor spread and invasiveness in vitro (Cos et al.1998). Indeed, it has been suggested that melatonin acts as a naturally occurring anti-estrogen on tumor cells, as it down-regulates hormones responsible for the growth of hormone-dependent mammary tumors (Torres-Farfan 2003).

A high percentage of women with estrogen-receptor-positive breast cancer have low plasma melatonin levels (Brzezinski et al. 1997). There have been some studies demonstrating changes in melatonin levels in breast cancer patients; specifically, women with breast cancer were found to have lower melatonin levels than women without breast cancer (Oosthuizen et al. 1989). Normally, women undergo a seasonal variation in the production of certain hormones, such as melatonin. However, it was found that women with breast cancer did not have a seasonal variation in melatonin levels, as did the healthy women (Holdaway et al. 1997).

Low levels of melatonin have been associated with breast cancer occurrence and development. Women who work predominantly at night and are exposed to light, which inhibits melatonin production and alters the circadian rhythm, have an increased risk of breast cancer development (Schernhammer et al. 2003).   Disruption of circadian rhythm is commonly observed among breast cancer patients (Mormont et al. 1997; Roenneberg et al. 2002) and contributes to cancer development and tumor progression. The circadian rhythm alone is a statistically significant predictor of survival time for breast cancer patients (Sephton et al. 2000).

Melatonin differs from the classic anti-estrogens such as tamoxifen in that it does not seem to bind to the estrogen receptor or interfere with the binding of estradiol to its receptor (Sanchez-Barcelo 2003). Melatonin does not cause side effects, such as those caused by the conventional anti-estrogen drug tamoxifen. Furthermore, when melatonin and tamoxifen are combined, synergistic benefits occur. Moreover, melatonin can increase the therapeutic efficacy of tamoxifen (Lissoni et al.1995) and biological therapies such as IL-2 (Lissoni et al. 1994).

How melatonin interferes with estrogen signaling is unknown, though recent studies suggest that it acts through a cyclic adenosine monophosphate (cAMP)-independent signaling pathway (Torres-Farfan 2003). It has been proposed that melatonin suppresses the epidermal growth factor receptor (EGF-R) (Blask et al. 2002) and exerts its growth inhibitory effects by inducing differentiation (“normalizing” cancer cells)(Cos et al. 1996). Melatonin directly inhibits breast cancer cell proliferation (Ram et al. 2000) and boosts the production of immune components, including natural killer cells (NK cells) that have an ability to kill metastasized cancer cells.

In studies, melatonin reduced the incidence and growth rate of breast tumors and slowed breast cancer development (Subramanian et al. 1991). Furthermore, prolonged oral melatonin administration significantly reduced the development of existing mammary tumors in animals (Rao et al. 2000).

In vitro experiments carried out with the ER-positive human breast cancer cells (MCF-7 cells), demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastatic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness. Further, this effect is mediated, at least in part, by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and beta (1)-integrin (Sanchez-Barcelo et al. 2003).

Melatonin can be safely taken for an indefinite period of time. The suggested dose of melatonin for breast cancer patients is 3-50 mg at bedtime. Initially, if melatonin is taken in large doses vivid dreams and morning drowsiness may occur. To avoid these minor side effects melatonin may be taken in low doses nightly and the dose slowly increased over a period of several weeks.

 

Pomegranate

Pomegranate, which is rich in antioxidants, has gained widespread popularity as a functional food (i.e., has health benefits). The health benefits of the fruit, juice and extract have been studied in relation to a variety of chronic diseases, including cancer (Syed 2012; Johanningsmeier 2011).

Researchers discovered that consumption of whole pomegranate seed oil and juice concentrate (Kim 2002) resulted in dramatic growth inhibition of estrogen-dependent breast cancer cells. The same study showed inhibition of tumor formation in rodent cells exposed to known breast carcinogens. Using different methods, another research group found a 42% reduction in tumor formation with whole pomegranate juice polyphenols and an 87% reduction with pomegranate seed oil (Mehta 2004).

Pomegranate seed oil is a potent inhibitor of aromatase, the enzyme that converts testosterone into estrogen (Adams 2010). This enzymatic blockade contributes to pomegranate seed oil’s ability to inhibit growth of estrogen-dependent breast cancer cells. Pomegranate extract has also been shown to enhance the effects of the estrogen blocking drug tamoxifen, with the authors of a study stating that “…pomegranate combined with tamoxifen may represent a novel and a powerful approach to enhance and sensitize tamoxifen action” (Banerjee 2011). Pomegranate also increases apoptosis, even in cancer cells that lack estrogen receptors (Kim 2002).

Cancer cells need to grow new blood vessels to support their rapid growth and tissue invasion (angiogenesis). They typically do this by ramping up production of a variety of growth factors, including VEGF and inflammatory interleukins. Pomegranate seed oil powerfully inhibits production of VEGF while upregulating production of migratory inhibitory factor (MIF) in breast cancer cells. In a laboratory model of vessel growth, these modulations translated into a significant decrease in new blood vessel formation (Toi 2003). Pomegranate seed oil’s capacity to block breast cancer development was also demonstrated in an organ culture model of mouse breast cancer (Mehta 2004). Treating the glands with pomegranate seed oil prior to exposure to a powerful carcinogen resulted in a 87% reduction in the number of cancerous lesions compared with controls.

Pomegranate seed oil contains a number of unique chemical constituents with potent biological effects. Punicic acid, an omega-5 polyunsaturated fatty acid that inhibits both estrogen-dependent and estrogen-independent breast cancer cell proliferation in lab cultures (Grossmann 2010), also induced apoptosis at rates up to 91% higher than those in untreated cell cultures—effects which appear to be related to fundamental regulation of cancer cell signaling pathways (Grossmann 2010).

 

PSK

PSK, which is a specially prepared polysaccharide extract from the mushroom Coriolus versicolor, has been studied extensively in Japan where it is used as a non-specific biological response modifier to enhance the immune system in cancer patients (Koda 2003; Noguchi 1995; Yokoe 1997). PSK suppresses tumor cell invasiveness by down-regulating several invasion-related factors (Zhang 2000). PSK has been shown to enhance NK cell activity in multiple studies (Ohwada 2006; Fisher 2002; Garcia-Lora 2001; Pedrinaci 1999).

In a study investigating the use of PSK in women with stage 2 breast cancer, post-operative participants received Tamoxifen with PSK (3 g daily) or Tamoxifen alone. The 5-year survival was 89.9% in the PSK group compared to 86.9% in the group receiving Tamoxifen only (Morimoto 1996).

 

Pterostilbene

Pterostilbene, a polyphenol found in blueberries, grapes, and in the bark of the Indian Kino Tree, is closely related to resveratrol (but with unique attributes). Pterostilbene’s mechanisms of action include blocking enzymes that activate carcinogens (Mikstacka 2006, 2007), inducing apoptosis (Tolomeo 2005) and cell cycle arrest (Wang 2012), and enhancing nitric oxide-induced cell death (Ferrer 2007).

Researchers observed that pterostilbene markedly inhibited the growth of breast cancer cells in the laboratory by inducing apoptosis and cell cycle arrest (Wang 2012).

 

Quercetin

Quercetin is a flavonoid found in a broad range of foods, from grape skins and red onions to green tea and tomatoes. Quercetin’s antioxidant and anti-inflammatory properties protect cellular DNA from cancer-inducing mutations (Aherne 1999). Quercetin traps developing cancer cells in the early phases of their replicative cycle, effectively preventing further malignant development and promoting cancer cell death (Yang 2006). Furthermore, quercetin favorably modulates chemical signaling pathways that are abnormal in cancer cells (Morrow 2001; Bach 2010).

In breast cancer cells, quercetin induces apoptosis and cell cycle arrest (Choi 2001; Chou 2010). Querctin inhibited the growth of tumors (Zhong 2003) and prolonged survival of mice with breast cancer (Du 2010).

 

Se-Methylselenocysteine

Se-methylselenocysteine (SeMSC), a naturally occurring organic selenium compound found to be an effective chemopreventive agent, is a new and better form of selenium. SeMSC is a selenoamino acid that is synthesized by plants such as garlic and broccoli. Methylselenocysteine (MSC) has been shown to be effective against mammary cell growth both in vivo and in vitro (Sinha et al. 1999) and has significant anticancer activity against mammary tumor development (Sinha et al. 1997). Moreover, Se-methylselenocysteine was one of the most effective selenium chemoprevention compounds and induced apoptosis in human leukemia cells (HL-60) in vitro (Jung et al. 2001a). Exposure to MSC blocks expansion of cancer colonies and premalignant lesions at an early stage by simultaneously modulating pathways responsible for inhibiting cell proliferation and enhancing apoptosis (Ip 2001).

Se-methylselenocysteine has been shown to:

• Produce a 33% better reduction of cancerous lesions than selenite.
• Produce a 50% decrease in tumor development.
• Induce cell death (apoptosis) in cancer cells.
• Inhibit cancer-cell growth (proliferation).
• Reduce density and development of tumor blood vessels.
• Down-regulate VEGF (vascular endothelial growth factor)(Ip et al. 1992; Sinha et al. 1997; Sinha et al. 1999; Ip et al. 2001; Dong et al. 2001)

Unlike MSC, which is incorporated into protein in place of methionine, SeMSC is not incorporated into any protein, thereby offering a completely bioavailable compound. In animal studies, SeMSC has been shown to be 10 times less toxic than any other known form of selenium. Breast cancer patients may consider taking 400 mcg of SeSMC daily.

 

Sulforaphane

Sulforaphane, which is an isothiocyanate, is most highly concentrated in broccoli as well as in other cruciferous vegetables (eg, brussels sprouts, cabbage and cauliflower).

Sulforaphane detoxifies potential carcinogens, promotes apoptosis, blocks the cell cycle that is required for cancer cell replication, prevents tumor invasion into healthy tissue, enhances natural killer cell activity, and combats metastasis (Zhang 2007; Nian 2009; Traka 2008; Thejass 2006). Research has also demonstrated that sulforaphane is among the plant chemicals most potently capable of blocking the cancer-producing effects of ultraviolet radiation (Dinkova-Kostova 2008).

It has been observed that sulforaphane activated apoptosis (Pledgie-Tracy 2007) and inhibited the proliferation of breast cancer cells in culture (Ramirez 2009; Jo 2007). Researchers have also noted that sulforaphane down-regulates the expression of estrogen receptor alpha in breast cancer cells (Ramirez 2009).

In another clinical trial, mice injected with breast cancer cells developed 60% less tumor mass when treated with sulforaphane compared to untreated mice (Jackson 2004).

 

CoQ10

Coenzyme Q10 (CoQ10) is synthesized in humans from tyrosine through a cascade of eight aromatic precursors. These precursors require eight vitamins, which are vitamin C, B2, B3 (niacin) B6, B12, folic acid, pantothenic acid, and tetrahydrobiopterin as their coenzymes.

Since the 1960s, studies have shown that cancer patients often have decreased blood levels of coenzyme Q10 (Lockwood et al. 1995; Folkers 1996; Ren et al. 1997). In particular, breast cancer patients (with infiltrative ductal carcinoma) who underwent radical mastectomy were found to have significantly decreased tumor concentrations of CoQ10 compared to levels in normal surrounding tissues. Increased levels of reactive oxygen species may be involved in the consumption of CoQ10 (Portakal et al. 2000). These findings sparked interest in the compound as a potential anticancer agent (NCCAM 2002). Cellular and animal studies have found evidence that CoQ10 stimulates the immune system and can increase resistance to illness (Bliznakov et al. 1970; Hogenauer et al. 1981; NCCAM 2002).

CoQ10 may induce protective effect on breast tissue and has demonstrated promise in treating breast cancer. Although there are only a few studies, the safe nature of CoQ10 coupled with this promising research of its bioenergetic activity suggests that breast cancer patients should take 100 mg up to 3 times a day.

In a clinical study, 32 patients were treated with CoQ10 (90 mg) in addition to other antioxidants and fatty acids; six of these patients showed partial tumor regression. In one of these cases the dose of CoQ10 was increased to 390 mg and within one month the tumor was no longer palpable, within two months the mammography confirmed the absence of tumor. In another case, the patient took 300 mg of CoQ10 for residual tumor (post non-radical surgery) and within 3 months there was non-residual tumor tissue (Lockwood et al. 1994). This overt complete regression of breast tumors in the latter two cases coupled with further reports of disappearance of breast cancer metastases (liver and elsewhere) in several other case (Lockwood et al. 1995) demonstrates the potential of CoQ10 in the adjuvant therapy of breast cancer.

There are promising results for the use of CoQ10 in protecting against heart damage related to chemotherapy. Many chemotherapy drugs can cause damage to the heart (UTH 1998; ACS 2000; NCCAM 2002; Dog et al. 2001), and initial animal studies found that CoQ10 could reduce the adverse cardiac effects of these drugs (Combs et al. 1977; Choe et al. 1979; Lubawy et al. 1980; Usui et al. 1982; Shinozawa et al. 1993; Folkers 1996).

Caution: Some studies indicate that CoQ10 should not be taken at the same time as chemotherapy. If this were true, it would be disappointing, because CoQ10 is so effective in protecting against adriamycin-induced cardiomyopathy. Adriamycin is a chemotherapy drug sometimes used as part of a chemotherapy cocktail. Until more research is known, it is not possible to make a definitive recommendation concerning taking CoQ10 during chemotherapy.

 

EPA and DHA

Dietary polyunsaturated fatty acids (PUFAs) of the omega-6 (n-6) class, found in corn oil and safflower oil, may be involved in the development of breast cancer, whereas long chain (LC) omega-3 (n-3) PUFAs, found in fish oil can inhibit breast cancer (Bagga et al. 2002).

A case control study examining levels of fatty acids in breast adipose tissue of breast cancer patients has shown that total omega-6 PUFAs may be contributing to the high risk of breast cancer in the United States and that omega-3 PUFAs, derived from fish oil, may have a protective effect (Bagga et al. 2002).

A higher omega-3:omega-6 ratio (n-3:n-6 ratio) may reduce the risk of breast cancer, especially in premenopausal women (Goodstine et al. 2003). In a prospective study of 35,298 Singapore Chinese women aged 45-74 years, it was determined that high levels of dietary omega-3 fatty acids from marine sources (fish/shellfish) were significantly associated with reduced risk of breast cancer. Furthermore, women who consumed low levels of marine omega-3 fatty acids had a statistically significant increased risk of breast cancer (Gago-Dominguez et al. 2003).

Omega-3 fatty acids, primarily eicosapentanoic acid (EPA) and docosahexaneoic acid (DHA) found naturally in oily fish and fish oil, have been consistently shown to retard the growth of breast cancer in vitro and in animal experiments, inhibit tumor development and metastasis. Fish oils have antiproliferative effects at high doses, which means they can inhibit tumor cell growth, through a free radical-mediated mechanism, while at more moderate doses omega-3 fatty acids inhibit Ras protein activity, angiogenesis, and inflammation. The production of pro-inflammatory cytokines can be modified by dietary omega-3 PUFAs (Mancuso et al. 1997).

High consumption of fatty fish is weakly associated with reduced breast cancer risk (Goodstine et al. 2003). The recommended dosage is to consume a fish-oil concentrate supplement that provides 3200 mg of EPA and 2400 mg of DHA a day taken in divided doses.

 

Vitamins A, D, and E

Vitamin A and vitamin D3 inhibit breast cancer cell division and can induce cancer cells to differentiate into mature, noncancerous cells. Vitamin D3 works synergistically with tamoxifen (and melatonin) to inhibit breast cancer cell proliferation. The vitamin D3 receptor as a target for breast cancer prevention was examined. Pre-clinical studies demonstrated that vitamin D compounds could reduce breast cancer development in animals. Furthermore, human studies indicate that both vitamin D status and genetic variations in the vitamin D3 receptor (VDR) may affect breast cancer risk. Findings from cellular, molecular and population studies suggest that the VDR is a nutritionally modulated growth-regulatory gene that may represent a molecular target for chemoprevention of breast cancer (Welsh et al. 2003).

Daily doses of vitamin A, 350,000 to 500,000 IU were given to 100 patients with metastatic breast carcinoma treated by chemotherapy. A significant increase in the complete response was observed; however, response rates, duration of response and projected survival were only significantly increased in postmenopausal women with breast cancer (Israel et al. 1985).

Breast cancer patients may take between 4000 to 6000 IU, of vitamin D3 every day. Water-soluble vitamin A can be taken in doses of 100,000-300,000 IU every day. Monthly blood tests are needed to make sure toxicity does not occur in response to these high daily doses of vitamin A and vitamin D3. After 4-6 months, the doses of vitamin D3 and vitamin A can be reduced.

Vitamin E is the term used to describe eight naturally occurring essential fat-soluble nutrients: alpha-, beta-, delta-, and gamma-tocopherols plus a class of compounds related to vitamin E called alpha-, beta-, delta-, and gamma-tocotrienols. Vitamin E from dietary sources may provide women with modest protection from breast cancer.

Vitamin E succinate, a derivative of fat-soluble vitamin E, has been shown to inhibit tumor cell growth in vitro and in vivo (Turley et al. 1997; Cameron et al. 2003). In estrogen receptor-negative human breast cancer cell lines vitamin E succinate inhibited growth and induced cell death. Since vitamin E is considered the main chain breaking lipophilic antioxidant in plasma and tissue, its role as a potential chemo-preventative agent and its use in the adjuvant treatment of aggressive human breast cancers appears reasonable. Those with estrogen-receptor-negative breast cancers should consider taking 800-1200 IU of vitamin E succinate a day. Vitamin E supplementation, 800 IU daily for 4 weeks, was shown to significantly reduce hot flashes in breast cancer survivors (Barton et al. 1998).

Caution: Be cautious about vitamin A toxicity when taking extremely high doses. When taking doses of vitamin D3 in excess of 1400 IU a day, regular blood chemistry tests should be taken to monitor kidney function and serum calcium metabolism. Vitamin E has potential blood thinning properties, individuals taking anticoagulant drugs should inform their treating physician if supplementing with vitamin E and have their clotting factors monitored regularly.

 

Tocotrienols

When vitamin E was isolated from plant oils, the term tocopherols was used to name the initial four compounds that shared similar structures. Their structures have two primary parts--a complex ring and a phytyl (long-saturated) side chain--and have been designated as alpha, beta, delta, and gamma tocopherol. Tocopherols (vitamin E) are important lipid-soluble antioxidants that can protect the body against free radical damage.

However, there are four additional compounds related to tocopherols--called tocotrienols that are less widely distributed in nature. The tocotrienol structure, three double bonds in an isoprenoid (unsaturated) side chain, differs from that of tocopherols. While tocopherols are found in corn, olive oil, and soybeans, tocotrienols are concentrated in palm, rice bran, and barley oils.

Tocotrienols elicit powerful anticancer properties, and studies have confirmed tocotrienol activity is much stronger than that of tocopherols (Schwenke et al. 2002).

Tocotrienols provide more efficient penetration into tissues such as the brain and liver. Tocotrienols move freely and more efficiently within cell membranes than tocopherols, giving tocotrienols greater ability to counteract free radicals. This greater mobility also allows tocotrienols to recycle more quickly than alpha-tocopherol. Tocotrienols are better distributed in fatty cell membranes and demonstrate greater antioxidant and free-radical-scavenging effects than that of vitamin E (alpha-tocopherol) (Serbinova et al. 1991; Theriault et al. 1999).

Tocotrienol's antioxidant function is associated with lowering DNA damage, tumor formation, and of cell damage. Animals exposed to carcinogens that were fed corn oil- or soybean oil-based diets had significantly more tumors than those fed a tocotrienol-rich palm oil diet. Tocotrienol-rich palm oil did not promote chemically induced breast cancer (Sundram et al. 1989).

Tocotrienols possess the ability to stimulate the selective killing of cancer cells through programmed cell death (apoptosis) and to reduce cancer cell proliferation while leaving normal cells unaffected (Kline et al. 2001). Tocotrienols are thought to suppress cancer through the isoprenoid side chain.

Tocotrienols cause growth inhibition of breast cancer cells in culture independent of estrogen sensitivity and have great potential in the prevention and treatment of breast cancer (Nesaretnam et al. 1998).

In vitro studies have demonstrated the effectiveness of tocotrienols as inhibitors of both estrogen-receptor-positive (estrogen-responsive) and estrogen-receptor-negative (nonestrogen-responsive) cell proliferation. The effect of palm tocotrienols on three human breast cancer cells lines, estrogen-responsive and estrogen-nonresponsive (MCF7, MDA-MB-231, and ZR-75-1), found that tocotrienols inhibited cell growth strongly in both the presence and absence of estradiol. The gamma- and delta-fractions of tocotrienols were most effective at inhibiting cell growth, while alpha-tocopherol was ineffective. Tocotrienols were found to enhance the effect of tamoxifen (Nesaretnam et al. 2000).

Delta-tocotrienol was shown to be the most potent inducer of apoptosis (programmed cell death) in both estrogen-responsive and estrogen-nonresponsive human breast cancer cells, followed by gamma- and alpha-tocotrienol (beta-tocotrienol was not tested). Interestingly, delta-tocotrienol is more plentiful in palm tocotrienols than in tocotrienols derived from rice. Of the natural tocopherols, only delta-tocopherol showed any apoptosis-inducing effect, although it was less than one tenth of the effect of palm and rice delta-tocotrienol (Yu et al. 1999).

Tocotrienols effectively arrested the cell cycle and triggered cell death of mammary cancer cells (from mice) whereas tocopherols (alpha, gamma, and delta) did not cause inhibition of tumor cell growth. Highly malignant cells were most sensitive to the antiproliferative effects of tocotrienols, whereas less aggressive precancerous cells were the least sensitive (McIntyre et al. 2000).

Tocotrienols were found to be far more effective than alpha-tocopherol in inhibiting breast cancer cell growth. Tocotrienols in combination with tamoxifen proved more effective than either compound alone in both estrogen-responsive and nonresponsive breast cancer cells. The synergism between tamoxifen and tocotrienols may reduce the risk of adverse side effect from tamoxifen (Guthrie et al. 1997).

Tocotrienols are considered important lipid-soluble antioxidants, with potent anticancer and anti-inflammatory activity. Therefore, a daily dose of 240 mg of tocotrienols should be considered as an adjuvant breast cancer therapy.

 

 

Cancer has an appetite for sugar and requires sugar for survival. Sugar plays an active role in reducing the immune response and energizes cancer, as tumors are primarily obligate glucose metabolizers.

There is a relationship between lactic acid, insulin, and angiogenesis. In tumors, hypoxic conditions occur through both inflammation, which reduces blood flow, and the chaotic development of blood vessels within tumors. These hypoxic conditions alter the pathways by which immune cells and tumor cells burn fuel (glucose) for energy, creating excessive lactic acid. In an oxygen-rich (aerobic) environment, glucose is burned in an efficient process that produces a maximum amount of energy and a minimal amount of lactic acid. However, tumor cells in chronic hypoxic conditions produce excessive lactic acid and inefficient utilization of glucose. Thus, there is a vicious cycle in which the reduced energy output stimulates the tumor cells to burn more glucose, which in turn produces more lactic acid. Tumor cells consume glucose at a rate three to five times higher than normal cells, creating a highly stimulated glycolysis (glucose-burning) pathway.

This glucose consumption can waste the cancer patient's energy reserves, and the increased production of lactic acid can stimulate increased production of angiogenic factors. Insulin plays an active role in promoting angiogenesis (the building of new blood vessels from existing blood vessels). Insulin is a growth factor that stimulates glycolysis and the proliferation of many cancer-cell lines through tyrosine kinase growth factors (Boyd 2003). In cancer patients, elevated levels of insulin are common in cancerous tissue and blood plasma. Obesity, and early stages of Type-II noninsulin-dependent diabetes mellitus (NIDDM), has been implicated as risk factors in a variety of cancers.

Based upon cancer's sugar dependency, a sugar-deprivation diet is strongly recommended. An effective way to eliminate sugar from the diet is to eat foods with a low Glycemic Index, such as vegetables, protein, and grains, are suggested.

With regard to depleting sugar from the diet, the following should be considered:

• Limit or avoid all white foods, including (but not limited to) sugar, flour, rice, pasta, breads, crackers, cookies, etc.
• Read labels. Sugar has many names (brown sugar, corn syrup, honey, molasses, maple syrup, high-fructose corn syrup, dextrin, raw sugar, fructose, polyols, dextrose, hydrogenated starch, galactose, glucose, sorbitol, fruit juice concentrate, lactose, brown rice syrup, xylitol, sucrose, mannitol, sorghum, maltose, and turbinado, to mention only a few).
• Limit all fruit juices – they contain a large amount of fructose (fruit sugar) but no fiber. Instead, eat low glycemic-rated fruit in small portions.

Natural compounds have also been reported to inhibit the cancer-promoting effects of insulin. For example, vitamin C has been reported to increase oxygen consumption and reduce lactic acid production in tumor cells. Other natural compounds that can reduce insulin resistance include omega-3 fatty acids, curcumin, flavonoids, selenium, and vitamin E.

As discussed earlier, estrogen is a growth factor for most breast cancers. High-fat diets and associated increases in fat tissue can increase estrogen availability in a number of ways:

• Fat tissue is a major source of estrogen production in postmenopausal women. Therefore, there is an association between high body weight and decreased survival in breast cancer patients.
• Obesity and possibly insulin resistance can decrease the levels of sex hormone binding globulin (SHBG) in both men and women and increase breast cancer risk or cancer progression.
• Obesity can alter liver metabolism of estrogen, allowing the retention of high estrogen byproducts with high estrogenic activity within the body.

Another consideration when discussing diet and breast cancer is the reduction of dietary estrogen. Several foods contain naturally occurring hormones (found in animal sources); synthetic hormones that can mimic estrogen in the human body (found in commercially packaged meat, poultry, and dairy products); or naturally estrogenic properties that can encourage the body's production of estrogens. Regardless of the source, try to avoid all commercial animal products (including, but not limited to, meats, poultry, and dairy). Also avoid the use of soft plastic food-storage products that can give off large amounts of polymers (e.g., by leaching into food contents), thought by environmentalists and some researchers to be a possible cause of breast cancer.

In order to reduce estrogen, a breast cancer patient should consider increasing dietary intake of fish high in omega-3 fatty acids, whey, eggs, and nuts, occasionally including hormone-free poultry and hormone-free, low-fat dairy products.

 

 

Current research supports using nutritional supplementation to improve the efficacy of chemotherapy drugs and radiotherapy. In fact, combining certain supplements can create a synergism that can effectively block or impede certain cancer pathways.

Therefore, the supplementation regimen following is suggested. Please read the section on Nutrients &  Rationale before considering this regimen because there are certain cautions to consider.

• Apigenin: 20 – 50 mg daily.
• Astragalus: 2000 – 4000 mg daily.
• Blueberry: 900 – 1800 mg daily.
• Chrysin: 1000 – 2000 mg daily.
• Coffee: 400 mg, three times daily.
• Cruciferous vegetable extract: 1 – 2 capsules per day.
• Curcumin: 400 mg three times daily (as highly absorbable BCM-95™).
• Lightly caffeinated green tea extract: three 725 mg capsules, two times a day with meals. Use decaffeinated green tea extract if you are sensitive to caffeine or want to use a less-stimulating version with the evening dosage.
• CLA or CLA with guarana: 3000 – 4000 mg daily of CLA and about 300 mg of guarana, early in the day.
• Lignans: 75 – 125 mg daily.
• Melatonin: 3 – 50 mg at bedtime.
• Pomegranate: 280 – 375 mg daily of punicalagins.
• Powders (broccoli, cabbage, and other cruciferous vegetables that provide sulforaphane and other cancer-fighting plant extracts): 1 – 2 tbsp daily.
• PSK (from the mushroom Coriolus versicolor): 3 g daily.
• Pterostilbene: 1 – 3 mg daily.
• Quercetin: 1000 – 3000 mg daily.
• Se-methylselenocysteine: 200 – 400 mcg daily.
• Sulforaphane: 400 – 1600 mg daily of a broccoli extract.
• CoQ10 (as ubiquinol): three 100 mg softgels in divided doses. Note the caution stated in this protocol.
• EPA/DHA (with sesame lignans): 2 - 4 grams daily. Take with nonfiber meals.
• Vitamin D3: 4000 – 6000 IU taken daily with monthly blood testing to monitor for toxicity. Reduce dosage at 6 months.
• Water-soluble vitamin A: 100 000 – 300 000 IU daily with monthly blood testing to monitor for toxicity. Reduce dosage at 6 months.
• Vitamin E: succinate (tocopheryl succinate), 1200 IU daily.
• Gamma tocopherol: 1 capsule daily.
• Vitamin C: 4000 – 12 000 mg throughout the day.
• Gamma linolenic acid: 299 - 1495 mg daily
• Whey protein concentrate-isolate: 30 – 60 g daily in divided doses.
• Calcium: 1000 - 1200 mg daily
• Magnesium: 200 - 1000 mg daily
• Vitamin K: 10 mg daily.
• Silicon: 6 mg daily.
• Multinutrient formula: daily.

 

 

ACS. American Cancer Institute. Learn About Cancer. What are the key statistics about breast cancer in men? http://www.cancer.org/cancer/breastcancerinmen/detailedguide/breast-cancer-in-men-key-statistics. Last updated 2/26/2015. Accessed 9/21/2015.

ACS. American Cancer Society's Guide to Complementary and Alternative Cancer Methods. 2000.

Adams LS, Kanaya N, Phung S, Liu Z, Chen S. Whole blueberry powder modulates the growth and metastasis of MDA-MB-231 triple negative breast tumors in nude mice. J Nutr. 2011 Oct;141(10):1805-12.

Adams LS, Phung S, Yee N, Seeram NP, Li L, Chen S. Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway. Cancer Res. 2010a May 1;70(9):3594-605.

Adams LS, Phung S, Yee N, Seeram NP, Li L, Chen S. Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway. Cancer Res. 2010b May 1;70(9):3594-605.

Adams LS, Zhang Y, Seeram NP, Heber D, Chen S. Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev Res (Phila). 2010c Jan;3(1):108-13.

Aherne SA, O'Brien NM. Protection by the flavonoids myricetin, quercetin, and rutin against hydrogen peroxide-induced DNA damage in Caco-2 and Hep G2 cells. Nutr Cancer. 1999;34(2):160-6.

Aiyer HS, Kichambare S, Gupta RC. Prevention of oxidative DNA damage by bioactive berry components. Nutr Cancer. 2008;60 Suppl 1:36-42.

Alberg AJ, Helzlsouer KJ. Epidemiology, prevention, and early detection of breast cancer. Curr Opin Oncol. 1997 Nov;9(6):505-11.

Alosi JA, McDonald DE, Schneider JS, Privette AR, McFadden DW. Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis. J Surg Res. 2010 Jun 15;161(2):195-201.

Arbiser JL, Klauber N, Rohan R, et al. Curcumin is an in vivo inhibitor of angiogenesis. Mol Med. 1998 Jun;4(6):376-83.

Bach A, Bender-Sigel J, Schrenk D, Flugel D, Kietzmann T. The antioxidant quercetin inhibits cellular proliferation via HIF-1-dependent induction of p21WAF. Antioxid Redox Signal. 2010 Aug 15;13(4):437-48.

Bageman E, Ingvar C, Rose C, et al. Coffee consumption and CYP1A2*1F genotype modify age at breast cancer diagnosis and estrogen receptor status. Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):895-901.

Bagga D, Anders KH, Wang HJ, et al. Long-chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast adipose tissue from women with and without breast cancer. Nutr Cancer. 2002;42(2):180-5.

Bakuradze T, Boehm N, Janzowski C, et al. Antioxidant-rich coffee reduces DNA damage, elevates glutathione status and contributes to weight control: results from an intervention study. Mol Nutr Food Res. 2011 May;55(5):793-7.

Banerjee S, Kambhampati S, Haque I, Banerjee SK. Pomegranate sensitizes Tamoxifen action in ER-α positive breast cancer cells. J Cell Commun Signal. 2011 Dec;5(4):317-24.

Barnwell JM, Arredondo MA, Kollmorgen D, et al. Sentinel node biopsy in breast cancer. Ann Surg Oncol. 1998 Mar;5(2):126-30.

Barton DL, Loprinzi CL, Quella SK, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol. 1998 Feb;16(2):495-500.

Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer. 2003 Nov 1;98(9):1802-10.

Belkaid A, Currie JC, Desgagnés J, et al. The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression. Cancer Cell Int. 2006 Mar 27;6:7.

Bergman JM, Thompson LU, Dabrosin C. Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo. Clin Cancer Res. 2007 Feb 1;13(3):1061-7.

Bierhaus A, Zhang Y, Quehenberger P, et al. The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B. Thromb Haemost. 1997 Apr;77(4):772-82.

Bitonti AJ MISFWJJEWP. Indole derivatives useful to treat estrogen-related neoplasms and disorders.1999(5,877,202).

Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2002 Feb;2(2):113-32.

Bliznakov E, Casey A, Premuzic E. Coenzymes Q: stimulants of the phagocytic activity in rats and immune response in mice. Experientia. 1970 Sep 26;26(9):953-4.

Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18(1):1-29.

Boyd DB. Insulin and cancer. Integr Cancer Ther. 2003 Dec;2(4):315-29.

Bradlow HL, Michnovicz J, Telang NT, et al. Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis. 1991 Sep;12(9):1571-4.

Brandi G, Paiardini M, Cervasi B, et al. A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines. Cancer Res. 2003 Jul 15;63(14):4028-36.

Brooks JD, Thompson LU. Mammalian lignans and genistein decrease the activities of aromatase and 17beta-hydroxysteroid dehydrogenase in MCF-7 cells. J Steroid Biochem Mol Biol. 2005 Apr;94(5):461-7.

Brzezinski A. Melatonin in humans. N Engl J Med. 1997 Jan 16;336(3):186-95.

Cameron IL, Munoz J, Barnes CJ, et al. High dietary level of synthetic vitamin E on lipid peroxidation, membrane fatty acid composition and cytotoxicity in breast cancer xenograft and in mouse host tissue. Cancer Cell Int. 2003 Mar 12;3(1):3.

Campbell DR, Kurzer MS. Flavonoid inhibition of aromatase enzyme activity in human preadipocytes. J Steroid Biochem Mol Biol. 1993 Sep;46(3):381-8.

Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989 Jan 1;63(1):181-7.

Chajes V, Lavillonniere F, Maillard V, et al. Conjugated linoleic acid content in breast adipose tissue of breast cancer patients and the risk of metastasis. Nutr Cancer. 2003;45(1):17-23.

Chen D, Landis-Piwowar KR, Chen MS, et al. Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts. Breast Cancer Res. 2007a;9(6):R80.

Chen I, Safe S, Bjeldanes L. Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem Pharmacol. 1996 Apr 26;51(8):1069-76.

Chen J, Stavro PM, Thompson LU. Dietary flaxseed inhibits human breast cancer growth and metastasis and downregulates expression of insulin-like growth factor and epidermal growth factor receptor. Nutr Cancer. 2002;43(2):187-92.

Chen LH, Fang J, Li H, Demark-Wahnefried W, Lin X. Enterolactone induces apoptosis in human prostate carcinoma LNCaP cells via a mitochondrial-mediated, caspase-dependent pathway. Mol Cancer Ther. 2007b Sep;6(9):2581-90.

Cho WC, Leung KN. In vitro and in vivo anti-tumor effects of Astragalus membranaceus. Cancer Lett. 2007b Jul 8;252(1):43-54.

Cho WC, Leung KN. In vitro and in vivo immunomodulating and immunorestorative effects of Astragalus membranaceus. J Ethnopharmacol. 2007a Aug 15;113(1):132-41.

Choe JY, Combs AB, Folkers K. Prevention by coenzyme Q10 of the electrocardiographic changes induced by adriamycin in rats. Res Commun Chem Pathol Pharmacol. 1979 Jan;23(1):199-202.

Choi EJ, Kim GH. 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol Rep. 2009 Dec;22(6):1533-7.

Choi JA, Kim JY, Lee JY, et al. Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol. 2001 Oct;19(4):837-44.

Chou CC, Yang JS, Lu HF, et al. Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch Pharm Res. 2010 Aug;33(8):1181-91.

Chu DT, Lepe-Zuniga J, Wong WL, LaPushin R, Mavligit GM. Fractionated extract of Astragalus membranaceus, a Chinese medicinal herb, potentiates LAK cell cytotoxicity generated by a low dose of recombinant interleukin-2. J Clin Lab Immunol. 1988 Aug;26(4):183-7.

Chujo H, Yamasaki M, Nou S, et al. Effect of conjugated linoleic acid isomers on growth factor-induced proliferation of human breast cancer cells. Cancer Lett. 2003 Dec 8;202(1):81-7.

Colditz GA. Epidemiology of breast cancer. Findings from the nurses' health study. Cancer. 1993 Feb 15;71(4 Suppl):1480-9.

Combs AB, Choe JY, Truong DH, et al. Reduction by coenzyme Q10 of the acute toxicity of adriamycin in mice. Res Commun Chem Pathol Pharmacol. 1977 Nov;18(3):565-8.

Cos S, Alvarez A, Mediavilla MD, et al. Influence of serum from healthy or breast tumor-bearing women on the growth of MCF-7 human breast cancer cells. Int J Mol Med. 2000 Jun;5(6):651-6.

Cos S, Fernandez R, Guezmes A, et al. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res. 1998 Oct 1;58(19):4383-90.

Cos S, Verduga R, Fernández-Viadero C, et al. Effects of melatonin on the proliferation and differentiation of human neuroblastoma cells in culture. Neurosci Lett. 1996 Sep;216(2):113-6.

Cover CM, Hsieh SJ, Cram EJ, et al. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res. 1999 Mar 15;59(6):1244-51.

Cover CM, Hsieh SJ, Tran SH, et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem. 1998 Feb 13;273(7):3838-47.

Cristofanilli M, Hortobagyi GN. Bisphosphonates in the Management of Breast Cancer. Cancer Control. 1999 May;6(3):241-6.

Davidson NE, Kennedy MJ. Protein kinase C and breast cancer. Cancer Treat Res. 1996;83:91-105.

Delmas PD. Bisphosphonates in the treatment of bone diseases. N Engl J Med. 1996 Dec 12;335(24):1836-7.

Deng Y, Chen HF. [Effects of Astragalus injection and its ingredients on proliferation and Akt phosphorylation of breast cancer cell lines]. Zhong Xi Yi Jie He Xue Bao. 2009 Dec;7(12):1174-80.

Devanaboyina U. Effects of indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced DNA adducts in rat mammary glands and liver (meeting abstract). Proc Annu Meet Am Assoc Cancer Res.1997(38):2427.

Devery R, Miller A, Stanton C. Conjugated linoleic acid and oxidative behaviour in cancer cells. Biochem Soc Trans. 2001 May;29(Pt 2):341-4.

Dinkova-Kostova AT. Phytochemicals as protectors against ultraviolet radiation: versatility of effects and mechanisms. Planta Med. 2008 Oct;74(13):1548-59.

Ditsch N, Mayer B, Rolle M, et al. Estrogen receptor expression profile of disseminated epithelial tumor cells in bone marrow of breast cancer patients. Recent Results Cancer Res. 2003;162:141-7.

Dog TL, Riley D, Carter T. Traditional and alternative therapies for breast cancer. Altern Ther Health Med. 2001 May;7(3):36-7.

Donegan WL. Common benign conditions of the breast. In Cancer of the Breast, Fourth Edition 1995.1995.

Dong Y, Lisk D, Block E, et al. Characterization of the biological activity of gamma-glutamyl-Se-methylselenocysteine: a novel, naturally occurring anticancer agent from garlic. Cancer Res. 2001 Apr 1;61(7):2923-8.

Du G, Lin H, Wang M, et al. Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1α in tumor and normal cells. Cancer Chemother Pharmacol. 2010 Jan;65(2):277-87.

Ellis MJ, Coop A, Singh B, et al. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res. 2003 Oct 1;63(19):6523-31.

Elmore JG, Miglioretti DL, Reisch LM, et al. Screening mammograms by community radiologists: variability in false-positive rates. J Natl Cancer Inst. 2002 Sep 18;94(18):1373-80.

Faria A, Pestana D, Teixeira D, et al. Blueberry anthocyanins and pyruvic acid adducts: anticancer properties in breast cancer cell lines. Phytother Res. 2010 Dec;24(12):1862-9.

Ferrer P, Asensi M, Priego S, et al. Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma. J Biol Chem. 2007 Feb 2;282(5):2880-90.

Feychting M, Osterlund B, Ahlbom A. Reduced cancer incidence among the blind. Epidemiology. 1998 Sep;9(5):490-4.

Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88.

Fisher M, Yang LX. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res. 2002 May;22(3):1737-54.

Folkers K. Relevance of the biosynthesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy. Biochem Biophys Res Commun. 1996 Jul 16;224(2):358-61.

Frankenberg-Schwager M, Garg I, Fran-Kenberg D, et al. Mutagenicity of low-filtered 30 kVp X-rays, mammography X-rays and conventional X-rays in cultured mammalian cells. Int J Radiat Biol. 2002 Sep;78(9):781-9.

Gago-Dominguez M, Yuan JM, Sun CL, et al. Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study. Br J Cancer. 2003 Nov 3;89(9):1686-92.

Gao X, Petroff BK, Oluola O, et al. Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation. Toxicol Appl Pharmacol. 2002 Sep 15;183(3):179-88.

Garcia-Lora A, Pedrinaci S, Garrido F. Protein-bound polysaccharide K and interleukin-2 regulate difference nuclear transcription factors in the NKL human natural killer cell line. Cancer Immunol Immunother. 2001 Jun;50(4):191-8.

Goldhirsch A, Wood WC, Gelber RD, et al. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol. 2003 Sep 1;21(17):3357-65.

Goodstine SL, Zheng T, Holford TR, et al. Dietary (n-3)/(n-6) fatty acid ratio: possible relationship to premenopausal but not postmenopausal breast cancer risk in U.S. women. J Nutr. 2003 May;133(5):1409-14.

Gordillo G, Fang H, Khanna S, Harper J, Phillips G, Sen CK. Oral administration of blueberry inhibits angiogenic tumor growth and enhances survival of mice with endothelial cell neoplasm. Antioxid Redox Signal. 2009 Jan;11(1):47-58.

Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802.

Grossmann ME, Mizuno NK, Schuster T, Cleary MP. Punicic acid is an omega-5 fatty acid capable of inhibiting breast cancer proliferation. Int J Oncol. 2010 Feb;36(2):421-6.

Grubbs CJ, Steele VE, Casebolt T, et al. Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res. 1995 May;15(3):709-16.

Gude RP, Menon LG, Rao SG. Effect of Caffeine, a xanthine derivative, in the inhibition of experimental lung metastasis induced by B16F10 melanoma cells. J Exp Clin Cancer Res. 2001 Jun;20(2):287-92.

Guthrie N, Gapor A, Chambers AF, et al. Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination. J Nutr. 1997 Mar;127(3):544S-8S.

Haigh PIGAE. A critical evaluation of sentinel lymph node dissection in malignancy.2000 Updates(14):1-11.

Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000 Apr;105(8):1045-7.

Hancock SL, Tucker MA, Hoppe RT. Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst. 1993 Jan 6;85(1):25-31.

Harris JRMMNL. Malignant tumors of the breast.1997( Section 2).

Hoelzl C, Knasmuller S, Wagner KH, et al. Instant coffee with high chlorogenic acid levels protects humans against oxidative damage of macromolecules. Mol Nutr Food Res. 2010 Dec;54(12):1722-33.

Hogenauer GMPDJ. The macrophage activating potential of ubiquinones. In Biomedical and Clinical Aspects of Coenzyme 1981, pp. 325-34.1981:325-34.

Holdaway IM, Mason BH, Gibbs EE, et al. Seasonal variation in the secretion of mammotrophic hormones in normal women and women with previous breast cancer. Breast Cancer Res Treat. 1997 Jan;42(1):15-22.

Holland JFKDWPRBRCJrFE. Holland-Frei Cancer Medicine.2000.

Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 1996 Dec 12;335(24):1785-91.

Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 1996 Dec 12;335(24):1785-91.

Huang TS, Lee SC, Lin JK. Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5292-6.

IOM.Institute of Medicine/Committee to Review the Department of Defense's Breast Cancer Research Program. A Review of the Department of Defense's Program for Breast Cancer Research 1997.1997.

Ip C, Banni S, Angioni E, et al. Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk in rats. J Nutr. 1999a Dec;129(12):2135-42.

Ip C, Dong Y. Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesion of the rat mammary gland. Anticancer Res. 2001 Mar;21(2A):863-7.

Ip C, Dong Y. Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland. Anticancer Res. 2001 Mar;21(2A):863-7.

Ip C, Ganther HE. Comparison of selenium and sulfur analogs in cancer prevention. Carcinogenesis. 1992 Jul;13(7):1167-70.

Ip MM, Masso-Welch PA, Ip C. Prevention of mammary cancer with conjugated linoleic acid: role of the stroma and the epithelium. J Mammary Gland Biol Neoplasia. 2003 Jan;8(1):103-18.

Ip MM, Masso-Welch PA, Shoemaker SF, et al. Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture. Exp Cell Res. 1999b Jul 10;250(1):22-34.

Israel L, Hajji O, Grefft-Alami A, et al. [Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients]. Ann Med Interne (Paris). 1985;136(7):551-4.

Jackson SJ, Singletary KW. Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor, which disrupts tubulin polymerization. Carcinogenesis. 2004 Feb;25(2):219-27.

Jee SH, Shen SC, Tseng CR, et al. Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells. J Invest Dermatol. 1998 Oct;111(4):656-61.

Jiang X, Lim LY, Daly JW, et al. Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs. Int J Oncol. 2000 May;16(5):971-8.

Jin UH, Lee JY, Kang SK, et al. A phenolic compound, 5-caffeoylquinic acid (chlorogenic acid), is a new type and strong matrix metalloproteinase-9 inhibitor: isolation and identification from methanol extract of Euonymus alatus. Life Sci. 2005 Oct 14;77(22):2760-9.

Jo EH, Kim SH, Ahn NS, et al. Efficacy of sulforaphane is mediated by p38 MAP kinase and caspase-7 activations in ER-positive and COX-2-expressed human breast cancer cells. Eur J Cancer Prev. 2007 Dec;16(6):505-10.

Johanningsmeier SD, Harris GK. Pomegranate as a functional food and nutraceutical source. Annu Rev Food Sci Technol. 2011;9:188-201.

Jung H. Is there a real risk of radiation-induced breast cancer for postmenopausal women? Radiat Environ Biophys. 2001c Jun;40(2):169-74.

Jung U, Zheng X, Yoon SO, et al. Se-methylselenocysteine induces apoptosis mediated by reactive oxygen species in HL-60 cells. Free Radic Biol Med. 2001a Aug 15;31(4):479-89.

Jung YD, Kim MS, Shin BA, et al. EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. Br J Cancer. 2001b Mar 23;84(6):844-50.

Katsube N, Iwashita K, Tsushida T, Yamaki K, Kobori M. Induction of apoptosis in cancer cells by Bilberry (Vaccinium myrtillus) and the anthocyanins. J Agric Food Chem. 2003 Jan 1;51(1):68-75.

Kemp MQ, Jeffy BD, Romagnolo DF. Conjugated linoleic acid inhibits cell proliferation through a p53-dependent mechanism: effects on the expression of G1-restriction points in breast and colon cancer cells. J Nutr. 2003 Nov;133(11):3670-7.

Kim ND, Mehta R, Yu W, et al. Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res Treat. 2002 Feb;71(3):203-17.

Kitamoto Y, Sakurai H, Mitsuhashi N, et al. Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line. Cancer Lett. 2003 Feb 28;191(1):101-7.

Kline K, Yu W, Sanders BG. Vitamin E: mechanisms of action as tumor cell growth inhibitors. J Nutr. 2001 Jan;131(1):161S-3S.

Koda K, Miyazaki M et al. A randomized controlled trial of postoperative adjuvant immunochemotherapy for colorectal cancer with oral medicines.Int J Oncol . 2003;23(1):165-72.

Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer--a multicenter validation study. N Engl J Med. 1998 Oct 1;339(14):941-6.

Kuhl CK, Schmutzler RK, Leutner CC, et al. Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. Radiology. 2000 Apr;215(1):267-79.

Kuo ML, Huang TS, Lin JK. Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. Biochim Biophys Acta. 1996 Nov 15;1317(2):95-100.

Li CI, Malone KE, Porter PL, et al. The relationship between alcohol use and risk of breast cancer by histology and hormone receptor status among women 65-79 years of age. Cancer Epidemiol Biomarkers Prev. 2003 Oct;12(10):1061-6.

Li J, Seibold P, Chang-Claude J. Coffee consumption modifies risk of estrogen-receptor negative breast cancer. Breast Cancer Res. 2011 May 14;13(3):R49.

Lissoni P, Barni S, Ardizzoia A, et al. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer. 1994 Feb 1;73(3):699-701.

Lissoni P, Brivio F, Brivio O, et al. Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients. J Biol Regul Homeost Agents. 1995 Jan;9(1):31-3.

Liu Y, Song X, Zhang D, et al. Blueberry anthocyanins: protection against ageing and light-induced damage in retinal pigment epithelial cells. Br J Nutr. 2011 Oct 12:1-12.

Lockwood K, Moesgaard S, Folkers K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10. Biochem Biophys Res Commun. 1994 Mar 30;199(3):1504-8.

Lockwood K, Moesgaard S, Yamamoto T, et al. Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases. Biochem Biophys Res Commun. 1995 Jul 6;212(1):172-7.

Lou YR, Lu YP, Xie JG, et al. Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B light. Nutr Cancer. 1999;33(2):146-53.

Love S. Dr. Susan Love's Breast Book.1997.

Lu YP, Lou YR, Xie JG, et al. Topical applications of caffeine or (-)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12455-60.

Lubawy WC, Dallam RA, Hurley LH. Protection against anthramycin-induced toxicity in mice by coenzyme Q10. J Natl Cancer Inst. 1980 Jan;64(1):105-9.

Mafuvadze B, Liang Y, Besch-Williford C, et al. Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-dependent BT-474 xenograft tumors. Horm Cancer. 2012 Aug;3(4):160-71.

Majumder B, Wahle KW, Moir S, et al. Conjugated linoleic acids (CLAs) regulate the expression of key apoptotic genes in human breast cancer cells. FASEB J. 2002 Sep;16(11):1447-9.

Mancuso P, Whelan J, DeMichele SJ, et al. Dietary fish oil and fish and borage oil suppress intrapulmonary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxic rats. Crit Care Med. 1997 Jul;25(7):1198-206.

Mani H, Sidhu GS, Kumari R, et al. Curcumin differentially regulates TGF-beta1, its receptors and nitric oxide synthase during impaired wound healing. Biofactors. 2002;16(1-2):29-43.

Marshall LM, Hunter DJ, Connolly JL, et al. Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer Epidemiol Biomarkers Prev. 1997 May;6(5):297-301.

Matchett MD, MacKinnon SL, Sweeney MI, Gottschall-Pass KT, Hurta RA. Blueberry flavonoids inhibit matrix metalloproteinase activity in DU145 human prostate cancer cells. Biochem Cell Biol. 2005 Oct;83(5):637-43.

McCann SE, Muti P, Vito D, et al. Dietary lignan intakes and risk of pre- and postmenopausal breast cancer. Int J Cancer. 2004 Sep 1;111(3):440-3.

McCann SE, Thompson LU, Nie J, et al. Dietary lignan intakes in relation to survival among women with breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study. Breast Cancer Res Treat. 2010 Jul;122(1):229-35.

McCarty MF. Activation of PPARgamma may mediate a portion of the anticancer activity of conjugated linoleic acid. Med Hypotheses. 2000 Sep;55(3):187-8.

McIntyre BS, Briski KP, Gapor A, et al. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exp Biol Med. 2000 Sep;224(4):292-301.

McNeil C. Sentinel node biopsy: studies should bring needed data. J Natl Cancer Inst. 1998 May 20;90(10):728-30.

Mehta R, Lansky EP. Breast cancer chemopreventive properties of pomegranate (Punica granatum) fruit extracts in a mouse mammary organ culture. Eur J Cancer Prev. 2004 Aug;13(4):345-8.

Meng Q, Qi M, Chen DZ, et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med. 2000;78(3):155-65.

Mercadante S, Serretta R, Casuccio A. Effects of caffeine as an adjuvant to morphine in advanced cancer patients. A randomized, double-blind, placebo-controlled, crossover study. J Pain Symptom Manage. 2001 May;21(5):369-72.

Michels KB, Holmberg L, Bergkvist L, et al. Coffee, tea, and caffeine consumption and breast cancer incidence in a cohort of Swedish women. Ann Epidemiol. 2002 Jan;12(1):21-6.

Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997 May 21;89(10):718-23.

Michnovicz JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer. 1991;16(1):59-66.

Mikstacka R, Przybylska D, Rimando AM, et al. Inhibition of human recombinant cytochromes P450 CYP1A1 and CYP1B1 by trans-resveratrol methyl ethers. Mol Nutr Food Res. 2007 May;51(5):517-24.

Mikstacka R, Rimando AM, Szalaty K, et al. Effect of natural analogues of trans-resveratrol on cytochromes P4501A2 and 2E1 catalytic activities. Xenobiotica. 2006 Apr;36(4):269-85.

Miller A, Stanton C, Devery R. Modulation of arachidonic acid distribution by conjugated linoleic acid isomers and linoleic acid in MCF-7 and SW480 cancer cells. Lipids. 2001 Oct;36(10):1161-8.

Misik M, Hoelzl C, Wagner KH, et al. Impact of paper filtered coffee on oxidative DNA-damage: results of a clinical trial. Mutat Res. 2010 Oct 13;692(1-2):42-8.

Mo H, Elson CE. Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr. 1999 Apr;129(4):804-13.

Mohammed HA, Ba LA, Burkholz T, et al. Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors. Nat Prod Commun. 2011 Jan;6(1):31-4.

Morimoto T, Ogawa M, Orita K et al. Postoperative adjuvant randomised trial comparing chemoendocrine therapy, chemotherapy and immunotherapy for patients with stage II breast cancer: 5-year results from the Nishinihon Cooperative Study Group of Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) of Japan. Eur J Cancer. 1996 Feb;32A(2):235-42.

Mormont MC, Levi F. Circadian-system alterations during cancer processes: a review. Int J Cancer. 1997 Jan 17;70(2):241-7.

Morrow DM, Fitzsimmons PE, Chopra M, et al. Dietary supplementation with the anti-tumour promoter quercetin: its effects on matrix metalloproteinase gene regulation. Mutat Res. 2001 Sep 1;480-481:269-76.

Mukhopadhyay S, Poddarr MK. Caffeine inhibits the development of Ehrlich ascites carcinoma cells in female mice. Indian J Exp Biol. 2001 Aug;39(8):735-41.

Muraoka K, Shimizu K, Sun X, et al. Flavonoids exert diverse inhibitory effects on the activation of NF-kappaB. Transplant Proc. 2002 Jun;34(4):1335-40.

Nagao K, Inoue N, Wang YM, et al. Conjugated linoleic acid enhances plasma adiponectin level and alleviates hyperinsulinemia and hypertension in Zucker diabetic fatty (fa/fa) rats. Biochem Biophys Res Commun. 2003 Oct 17;310(2):562-6.

National Cancer Institute. Public Health Service Department of Health and Human Services.2003

NCCAM. National Center for Complementary and Alternative Medicine. Cancer Facts: Complementary and Alternative Medicine: Questions and Answers about Coenzyme Q10. 2002.

NCCAM. National Center for Complementary and Alternative Medicine. Cancer Facts: Complementary and Alternative Medicine: Questions and Answers about Coenzyme Q10. 2002.

NCI. National Cancer Institute. Breast Cancer: PDQ Information for Health Care Professionals 1998.1998.

NCI. National Cancer Institute. SEER: Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Breast Cancer. http://seer.cancer.gov/statfacts/html/breast.html. Accessed 9/21/2015.

Nesaretnam K, Dorasamy S, Darbre PD. Tocotrienols inhibit growth of ZR-75-1 breast cancer cells. Int J Food Sci Nutr. 2000;51 Suppl:S95-103.

Nesaretnam K, Stephen R, Dils R, et al. Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Lipids. 1998 May;33(5):461-9.

Nguyen V, Tang J, Oroudjev E, et al. Cytotoxic effects of bilberry extract on MCF7-GFP-tubulin breast cancer cells. J Med Food. 2010 Apr;13(2):278-85.

Nian H, Delage B, Ho E, et al. Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds. Environ Mol Mutagen. 2009 Apr;50(3):213-21.

Nihira S. Development of HER2-specific humanized antibody Herceptin (trastuzumab). Nippon Yakurigaku Zasshi. 2003 Dec;122(6):504-14.

Noguchi K, Tanimura H et al. Polysaccharide preparation PSK augments the proliferation and cytotoxicity of tumor-infiltrating lymphocytes in vitro.Anticancer Res . 1995;15(2):255-8.

Ohwada S, Ogawa T, Makita F, et al. Beneficial effects of protein-bound polysaccharide K plus tegafur/uracil in patients with stage II or III colorectal cancer: analysis of immunological parameters. Oncol Rep. 2006 Apr;15(4):861-8.

ONI. Efficacy of adjunctive therapy with tamoxifen depends on tumor's hormone receptor status. Oncology News International.2004;2000 Jun(9):6.

Oosthuizen JM, Bornman MS, Barnard HC, et al. Melatonin and steroid-dependent carcinomas. Andrologia. 1989 Sep;21(5):429-31.

Page DL, Dupont WD, Rogers LW, et al. Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer. 1985 Jun 1;55(11):2698-708.

Park JI, Lee MG, Cho K, et al. Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene. 2003 Jul 10;22(28):4314-32.

Parker RA, Pearce BC, Clark RW, et al. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem. 1993 May 25;268(15):11230-8.

Patel D, Shukla, S, Gupta S. Apigenin and cancer chemoprevention: progress, potential and promise (review). Int J Oncol. 2007;30(1):233-45.

Pavlakis N, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2002;(1):CD003474.

Pedrinaci S, Algarra I, Garrido F. Protein-bound polysaccharide (PSK) induces cytotoxic activity in the NKL human natural killer cell line. Int J Clin Lab Res. 1999;29(4):135-40.

Pledgie-Tracy A, Sobolewski MD, Davidson NE. Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther. 2007 Mar;6(3):1013-21.

Plummer SM, Holloway KA, Manson MM, et al. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene. 1999 Oct 28;18(44):6013-20.

Portakal O, Ozkaya O, Erden IM, et al. Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients. Clin Biochem. 2000 Jun;33(4):279-84.

Qi W, Qiao D, Martinez JD. Caffeine induces TP53-independent G(1)-phase arrest and apoptosis in human lung tumor cells in a dose-dependent manner. Radiat Res. 2002 Feb;157(2):166-74.

Rahman KM, Aranha O, Sarkar FH. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr Cancer. 2003;45(1):101-12.

Ram PT, Yuan L, Dai J, et al. Differential responsiveness of MCF-7 human breast cancer cell line stocks to the pineal hormone, melatonin. J Pineal Res. 2000 May;28(4):210-8.

Ramirez MC, Singletary K. Regulation of estrogen receptor alpha expression in human breast cancer cells by sulforaphane. J Nutr Biochem. 2009 Mar;20(3):195-201.

Rao GN, Ney E, Herbert RA. Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with c-neu breast cancer oncogene. Breast Cancer Res Treat. 2000 Dec;64(3):287-96.

Reddy S, Aggarwal BB. Curcumin is a non-competitive and selective inhibitor of phosphorylase kinase. FEBS Lett. 1994 Mar 14;341(1):19-22.

Ren S, Lien EJ. Natural products and their derivatives as cancer chemopreventive agents. Prog Drug Res. 1997;48:147-71.

Requirand P, Gibert P, Tramini P, et al. Serum fatty acid imbalance in bone loss: example with periodontal disease. Clin Nutr. 2000 Aug;19(4):271-6.

Ribeiro JC, Barnetson AR, Jackson P, et al. Caffeine-increased radiosensitivity is not dependent on a loss of G2/M arrest or apoptosis in bladder cancer cell lines. Int J Radiat Biol. 1999 Apr;75(4):481-92.

Ricci MS, Toscano DG, Mattingly CJ, et al. Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells. J Biol Chem. 1999 Feb 5;274(6):3430-8.

Ries LAGEMPKCLealE. SEER Cancer Statistics Review 1973-1997.2000

Roemer-Becuwe C, Krakowski I, Conroy T. [Bisphosphonates, pain and quality of life in metastatic breast cancer patients: a literature review]. Bull Cancer. 2003 Dec;90(12):1097-105.

Roenneberg T, Lucas RJ. Light, endocrine systems, and cancer--a view from circadian biologists. Neuroendocrinol Lett. 2002 Jul;23 Suppl 2:82-3.

Rose C, Vtoraya O, Pluzanska A, et al. An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer. 2003 Nov;39(16):2318-27.

Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol. 1999 Nov;17(11):3631-52.

Sakurai H, Mitsuhashi N, Tamaki Y, et al. Interaction between low dose-rate irradiation, mild hyperthermia and low-dose caffeine in a human lung cancer cell line. Int J Radiat Biol. 1999 Jun;75(6):739-45.

Sanchez-Barcelo EJ, Cos S, Fernandez R, et al. Melatonin and mammary cancer: a short review. Endocr Relat Cancer. 2003 Jun;10(2):153-9.

Sanchez-Barcelo EJ, Cos S, Fernandez R, et al. Melatonin and mammary cancer: a short review. Endocr Relat Cancer. 2003 Jun;10(2):153-9.

Schernhammer ES, Laden F, Speizer FE, et al. Night-shift work and risk of colorectal cancer in the nurses' health study. J Natl Cancer Inst. 2003 Jun 4;95(11):825-8.

Schwartz GF, Giuliano AE, Veronesi U. Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast, April 19-22, 2001, Philadelphia, Pennsylvania. Cancer. 2002 May 15;94(10):2542-51.

Schwenke DC. Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer? J Nutr Biochem. 2002 Jan;13(1):2-20.

Seeram NP, Adams LS, Zhang Y, et al. Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro. J Agric Food Chem. 2006 Dec 13;54(25):9329-39.

Senie RT, Tenser SM. The timing of breast cancer surgery during the menstrual cycle. Oncology (Huntingt). 1997 Oct;11(10):1509-17.

Sephton SE, Sapolsky RM, Kraemer HC, et al. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000 Jun 21;92(12):994-1000.

Serbinova E, Kagan V, Han D, et al. Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Free Radic Biol Med. 1991;10(5):263-75.

Sharma OP. Antioxidant activity of curcumin and related compounds. Biochem Pharmacol. 1976 Aug 1;25(15):1811-2.

Shertzer HG, Berger ML, Tabor MW. Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol. Biochem Pharmacol. 1988 Jan 15;37(2):333-8.

Shinozawa S, Gomita Y, Araki Y. Protective effects of various drugs on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice and rats. Biol Pharm Bull. 1993 Nov;16(11):1114-7.

Sidhu GS, Singh AK, Thaloor D, et al. Enhancement of wound healing by curcumin in animals. Wound Repair Regen. 1998 Mar;6(2):167-77.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a cancer journal for clinicians. Jan-Feb 2015;65(1):5-29.

Sinha R, Kiley SC, Lu JX, et al. Effects of methylselenocysteine on PKC activity, cdk2 phosphorylation and gadd gene expression in synchronized mouse mammary epithelial tumor cells. Cancer Lett. 1999 Nov 15;146(2):135-45.

Sinha R, Medina D. Inhibition of cdk2 kinase activity by methylselenocysteine in synchronized mouse mammary epithelial tumor cells. Carcinogenesis. 1997 Aug;18(8):1541-7.

Sporn MB, Roberts AB, Wakefield LM, et al. Transforming growth factor-beta and suppression of carcinogenesis. Princess Takamatsu Symp. 1989;20:259-66.

Spratt JSTGR. In Gross Anatomy of the Breast. 1995 fourth edition.

Srinivasan C, Aiyer HS, Gupta RC. Dietary berries and ellagic acid diminish estrogen-mediated mammary tumorigenesis in ACI rats. Nutr Cancer. 2008;60(2):227-34.

Srivastava A, Akoh CC, Fischer J, Krewer G. Effect of anthocyanin fractions from selected cultivars of Georgia-grown blueberries on apoptosis and phase II enzymes. J Agric Food Chem. 2007 Apr 18;55(8):3180-5.

Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May 15;336(20):1401-8.

Subramanian A, Kothari L. Suppressive effect by melatonin on different phases of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced rat mammary gland carcinogenesis. Anticancer Drugs. 1991 Jun;2(3):297-303.

Sundram K, Khor HT, Ong AS, et al. Effect of dietary palm oils on mammary carcinogenesis in female rats induced by 7,12-dimethylbenz(a)anthracene. Cancer Res. 1989 Mar 15;49(6):1447-51.

Susman E. New drug outperforms tamoxifen. UPI Science News. 2001;Dec 11, 2001.

Syed DN, Chamcheu JC, Mukhtar VM. Pomegranate Extracts and Cancer Prevention: Molecular and Cellular Activies. Anticancer Agents Med Chem. 2012 Oct 12.

Taioli E, Garbers S, Bradlow HL, et al. Effects of indole-3-carbinol on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers. Cancer Epidemiol Biomarkers Prev. 1997 Jul;6(7):517-22.

Telang NT, Katdare M, Bradlow HL, et al. Inhibition of proliferation and modulation of estradiol metabolism: novel mechanisms for breast cancer prevention by the phytochemical indole-3-carbinol. Proc Soc Exp Biol Med. 1997 Nov;216(2):246-52.

Thejass P, Kuttan G. Augmentation of natural killer cell and antibody-dependent cellular cytotoxicity in BALB/c mice by sulforaphane, a naturally occurring isothiocyanate from broccoli through enhanced production of cytokines IL-2 and IFN-gamma. Immunopharmacol Immunotoxicol. 2006;28(3):443-57.

Theriault A, Chao JT, Wang Q, et al. Tocotrienol: a review of its therapeutic potential. Clin Biochem. 1999 Jul;32(5):309-19.

Thompson LU, Chen JM, Li T, et al. Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res. 2005 May 15;11(10):3828-35.

Toda S, Miyase T, Arichi H, et al. Natural antioxidants. III. Antioxidative components isolated from rhizome of Curcuma longa L. Chem Pharm Bull (Tokyo). 1985 Apr;33(4):1725-8.

Toi M, Bando H, Ramachandran C, et al. Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis. 2003;6(2):121-8.

Tolomeo M, Grimaudo S, Di Cristina A, et al. Pterostilbene and 3'-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells. Int J Biochem Cell Biol. 2005 Aug;37(8):1709-26.

Torres-Farfan C, Richter HG, Rojas-Garcia P, et al. mt1 Melatonin receptor in the primate adrenal gland: inhibition of adrenocorticotropin-stimulated cortisol production by melatonin. J Clin Endocrinol Metab. 2003 Jan;88(1):450-8.

Traka M, Gasper AV, Melchini A, et al. Broccoli consumption interacts with GSTM1 to perturb oncogenic signalling pathways in the prostate. PLoS One. 2008 Jul 2;3(7):e2568.

Travlos GS, Wilson RE, Murrell JA, et al. The effect of short intermittent light exposures on the melatonin circadian rhythm and NMU-induced breast cancer in female F344/N rats. Toxicol Pathol. 2001 Jan;29(1):126-36.

Tsuchiya H, Yamamoto N, Asada N, et al. Caffeine-potentiated radiochemotherapy and function-saving surgery for high-grade soft tissue sarcoma. Anticancer Res. 2000 May;20(3B):2137-43.

Turley JM, Fu T, Ruscetti FW, et al. Vitamin E succinate induces Fas-mediated apoptosis in estrogen receptor-negative human breast cancer cells. Cancer Res. 1997 Mar;57(5):881-90.

Turner RR, Ollila DW, Krasne DL, et al. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg. 1997 Sep;226(3):271-6.

USPSTF, U.S.Preventive Services Task Force. Guide to Clinical Preventive Services.1996 Second Edition.

Usui T, Ishikura H, Izumi Y, et al. Possible prevention from the progression of cardiotoxicity in adriamycin-treated rabbits by coenzyme Q10. Toxicol Lett. 1982 Jun;12(1):75-82.

UTH. University of Texas-Houston and Center for Alternative Medicine Research in Cancer. Hydrazine Sulfate 1998.1998

Valenzuela MT, Mateos S, Ruiz de Almodovar JM, et al. Variation in sensitizing effect of caffeine in human tumour cell lines after gamma-irradiation. Radiother Oncol. 2000 Mar;54(3):261-71.

Voorrips LE, Brants HA, Kardinaal AF, et al. Intake of conjugated linoleic acid, fat, and other fatty acids in relation to postmenopausal breast cancer: the Netherlands Cohort Study on Diet and Cancer. Am J Clin Nutr. 2002 Oct;76(4):873-82.

Wang C, Makela T, Hase T, Adlercreutz H, Kurzer MS. Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):205-12.

Wang Y, Ding L, Wang X, et al. Pterostilbene simultaneously induces apoptosis, cell cycle arrest and cyto-protective autophagy in breast cancer cells. Am J Transl Res. 2012;4(1):44-51.

Warner E, Plewes DB, Shumak RS, et al. Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol. 2001 Aug 1;19(15):3524-31.

Weaver DL, Krag DN, Ashikaga T, et al. Pathologic analysis of sentinel and nonsentinel lymph nodes in breast carcinoma: a multicenter study. Cancer. 2000 Mar 1;88(5):1099-107.

Welsh J, Wietzke JA, Zinser GM, et al. Vitamin D-3 receptor as a target for breast cancer prevention. J Nutr. 2003 Jul;133(7 Suppl):2425S-33S.

Whittemore AS. Risk of breast cancer in carriers of BRCA gene mutations. N Engl J Med. 1997 Sep 11;337(11):788-9.

Wittmann BM, Wang N, Montano MM. Identification of a novel inhibitor of breast cell growth that is down-regulated by estrogens and decreased in breast tumors. Cancer Res. 2003 Aug 15;63(16):5151-8.

Wong GY, Bradlow L, Sepkovic D, et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl. 1997;28-29:111-6.

Woolf SH. The accuracy and effectiveness of routine population screening with mammography, prostate-specific antigen, and prenatal ultrasound: a review of published scientific evidence. Int J Technol Assess Health Care. 2001;17(3):275-304.

Xu Y, Xin Y, Diao Y, et al. Synergistic Effects of Apigenin and Paclitaxel on Apoptosis of Cancr Cells. PLoS ONE 2011;6(12):e29169.

Yang JH, Hsia TC, Kuo HM, et al. Inhibition of lung cancer cell growth by quercetin glucuronides via G2/M arrest and induction of apoptosis. Drug Metab Dispos. 2006 Feb;34(2):296-304.

Yankaskas BC, Schell MJ, Bird RE, et al. Reassessment of breast cancers missed during routine screening mammography: a community-based study. AJR Am J Roentgenol. 2001 Sep;177(3):535-41.

Ye MN, Chen HF, Zhou RJ, Liao MJ. [Effects of Astragalus polysaccharide on proliferation and Akt phosphorylation of the basal-like breast cancer cell line]. Zhong Xi Yi Jie He Xue Bao. 2011 Dec;9(12):1339-46.

Yi W, Fischer J, Krewer G, Akoh CC. Phenolic compounds from blueberries can inhibit colon cancer cell proliferation and induce apoptosis. J Agric Food Chem. 2005 Sep 7;53(18):7320-9.

Yokoe T, Iino Y et al. HLA antigen as predictive index for the outcome of breast cancer patients with adjuvant immunochemotherapy with PSK.Anticancer Res . 1997;17(4A):2815-8.

Yu W, Simmons-Menchaca M, Gapor A, et al. Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr Cancer. 1999;33(1):26-32.

Zhang F, Altorki NK, Mestre JR, et al. Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells. Carcinogenesis. 1999 Mar;20(3):445-51.

Zhang H, Morisaki T et al. Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs.Clin Exp Metastasis . 2000;18(4):343-52.

Zhang X, Malejka-Giganti D. Effects of treatment of rats with indole-3-carbinol on apoptosis in the mammary gland and mammary adenocarcinomas. Anticancer Res. 2003 May;23(3B):2473-9.

Zhang Y, Tang L. Discovery and development of sulforaphane as a cancer chemopreventive phytochemical. Acta Pharmacol Sin. 2007 Sep;28(9):1343-54.

Zhong X, Wu K, He S, et al. [Effects of quercetin on the proliferation and apoptosis in transplantation tumor of breast cancer in nude mice]. [Article in Chinese] Sichuan Da Xue Xue Bao Yi Xue Ban. 2003 Jul;34(3):439-42.