Breast cancer is the most common cancer  in  North  American  women.  It makes up almost 30% of all female cancers and is the leading cause of death among women 40-55 years old.¹ There are numerous risk factors that are associated with breast cancer. However, one of the most well established is increased exposure to estrogen.² Women that experience early menarche and a later onset menopause have a higher risk of breast cancer due to the lengthened exposure to estrogen during their lifetime.³ External sources of estrogen such as hormone replacement therapy and the birth control pill have also been linked to increased breast cancer rates.³ Awareness about the impact and importance of estrogen is quickly growing because there are so many factors that can lead to increased exposure. Not only is estrogen made within the body, many chemicals found in the environment act like estrogen and also prevent its proper breakdown and metabolism. Fortunately, there are a number of dietary factors that promote the healthy function and  metabolism of estrogen and other hormones. This article will discuss the positive and negative forms of estrogen including phytoestrogens and xenoestrogens and how they relate to breast cancer. It will also address key dietary factors that help reduce breast cancer risk and promote hormonal balance.

Understanding estrogens

Estrogens are an  essential  family  of hormones that regulate many important functions, especially in the female reproductive system. While they are important, estrogen receptors often become saturated and over stimulated due to excess production, poor metabolism and exposure to environmental chemicals that have similar functions. This leads to the excessive promotion of cell growth, which ultimately contributes to cancer cell  growth.  To fully   understand   the role of estrogen in breast cancer development, we must look at the various forms and their actions since there is a wide range of functions and levels of activity. Estrogens exist  in the body in three different primary forms, estrone (E1), 17β-estradiol (E2), and 16α-estriol (E3).⁴ E2 is produced in  the ovaries and is considered the most potent estrogen. E2 is approximately 12 times more potent than E1  and  over 80 times more potent than E3 .⁴ Estrone (E1)  is  produced  primarily  in adipose tissue, especially after menopause. Estriol (E3) is formed in the liver through the conversion of E2 and E1.⁴ Unfortunately, a number of harmful foods, environmental toxins, and chemicals can block this conversion and therefore result in increased levels of E2, which can promote breast cancer growth.³ Since E3 is the weakest form of estrogen, it acts in a similar fashion to a plant phytoestrogen and blocks the estrogen receptor from being stimulated by the more potent E2 or xenoestrogens. Higher levels of E3 have been associated with lower breast cancer risk, while higher levels of E2 have shown increased cancer risk.⁴ During the metabolism of E2 and E1 in the liver, three main estrogen metabolites are formed: 2-hydroxyestrone (2- OHE1), 4-hydroxyestrone (4-OHE1), and 16α-hydroxyestrone (16α-OHE1).⁵ See Figure 1 for a diagram  of  estrogen metabolism in the liver. The 16α-OHE1 metabolites have a very potent stimulatory effect on estrogen receptors and they promote cell growth, which increases cancer risk.⁵ 4-OHE1 accumulates in the breast tissue and causes DNA mutations and suppresses the activity of p53, an anti-cancer gene.⁵ 2-hydroxyestrone opposes the  effects of the other 2 estrogen metabolites  and appears to have a protective effect in breast cancer.⁵ Recent studies have looked at the ratio of 2-OHE1 to 16α-OHE1 in urine and have found that higher ratios may have protective effects in breast cancer, but more studies are needed to confirm this ratio as a risk assessment tool.^6,7

Xenoestrogens

Xenoestrogens are a group of environmental chemicals which  mimic estrogen in the body. This family of molecules has been linked to the development and promotion of hormonally sensitive cancers. As of 2003 there were over 160 xenoestrogens that may be involved in breast cancer development.⁸ Cancer types associated with environmental  chemical   exposure and that have been well documented  in literature include those of the reproductive system, breast, lung, kidney,  pancreas,  and   brain.⁹  There is evidence that the  xenoestrogens play a role in in all phases of cancer development including initiation, transformation, and invasion.¹⁰ For example, a number of studies have now confirmed that a chemical (a polycyclic aromatic  hydrocarbon) produced during meat frying and grilling strongly increases DNA damage in breast cells and promotes breast cancer growth.¹¹ There is still more research to be done to fully understand the broad health impact of xenoestrogens, but the emerging evidence is very concerning due to their widespread prevalence and pervasiveness in our food products, water supply, and environment. As part of a hormonal balancing and breast cancer prevention plan, it is paramount to consider reducing the exposure to these compounds that contribute to detrimental estrogenic activity in the body.

Phytoestrogens and breast cancer

It is impossible to talk about breast cancer and estrogen without briefly discussing phytoestrogens. There is a fair amount of confusion about the safety and effectiveness of phytoestrogens, even among medical professionals. Phytoestrogens are a group of compounds found in  certain  plants that have an estrogen-like effect in the human body. These compounds interact with estrogen receptors, but they are much weaker than estradiol (E2) or most xenoestreogens.⁴ Due to their relative weakness, phytoestrogens may bind to the estrogen receptor without actually activating it, therefore preventing E2 or xenoesteogens from activating the receptor. This would explain the fact that the majority of studies have shown phytoestrogens to be protective against breast cancer, while elevated levels of human or synthetic estrogen increases the risk.¹² It is also important to recognize that there are two different types of estrogen receptors in the body: alpha-estrogen receptors (ER-α) and beta-estrogen receptors (ER-β). This is important because most phytoestrogens bind more strongly to ER-β than ER-α.¹³ ER-β receptors have been linked to increasing cancer cell apoptosis and are often down regulated in hormone sensitive cancers. Conversely, many xenoestrogens activate ER-α, which are present on 75% of breast cancer tumors.¹⁴ The fact that plant compounds such as quercetin selectively bind ER-β receptors suggests that some phytoestrogens may be useful in promoting cancer cell death.¹²

A large number of population studies that assess soy consumption found that higher intakes do not increase breast cancer risk. Some studies even showed a protective effect.¹⁵ After considering all the studies, a daily intake of 10g of soy protein had the optimal protective effect.¹⁵ These results are  opposed  by a number of test tube studies  that  have shown phytoestrogens in soy to stimulate estrogen receptors and breast cancer cell growth. The difference in the results highlights the complexity in phytoestrogen activity. One important point to consider is that individual differences  in  intestinal  microflora  in humans promote the formation of various phytoestrogen metabolites such as equol, which has a noted cancer protective effect.¹⁶ New data suggests that equol could possibly enhance the effect of tamoxifen in the prevention  of breast cancer.¹⁷ These factors are not considered in test tube studies and may be responsible for the negative results.

While there still is more research to be done, population studies suggest that moderate dietary consumption  does not  increase the risk of breast cancer.  It may even  be  protective,  especially if the person has consumed soy since childhood. It’s also important to remember that not all phytoestrogens are the same and some may offer a greater protective effect than others.

The Influence of Diet on Estrogen and Breast Cancer Risk Reduction

Fromadietaryperspective,cruciferous vegetables have demonstrated  the most  powerful  anti-cancer  effect. One study found that increasing the cruciferous vegetable intake of healthy postmenopausal women for four weeks increased urinary 2-OHE1:16α-OHE1 ratios, suggesting that high intakes of cruciferous vegetables can shift estrogen metabolism.¹⁸ Theses vegetables contain a group of natural compounds called glucosinolates (which are later converted to biologically active isothiocyanates) that support liver detoxification and hormone elimination pathways.  Two  of the most promising isothiocyanates with potential hormonal balancing activity include indole-3-carbinol (I3C) and sulforaphane.¹⁹

Sulforaphane

Sulforaphane is a compound with a unique ability to stimulate the phase 2 liver detoxification system.²⁰ The phase 2 pathway is very important since it is the final stage for the removal of harmful compounds, detoxification products, and excess estrogens. Sulforaphane also has an impressive range of anti-cancer activity beyond stimulating phase 2 detoxification including  stimulation  of cancer cell suicide, preventing replication, reducing tumor spreading and inhibiting blood supply to cancer cells.²¹ Numerous studies have shown that sulforaphane can prevent the growth of various cancer cells of the prostate, colon and breast.²¹ Perhaps the most exciting recently discovered action is that it may actually inhibit breast cancer stem cells which are responsible for continued tumor growth and disease relapse.²²Another promising anti-cancer effect is the ability of sulforaphane to reduce inflammation right at the genetic level by stimulating a control protein called nuclear factor 2 (Nrf2).¹⁹

From a practical perspective, cruciferous vegetables contain high amounts of glucoraphanin (also referred to as sulforaphane glucosinolate or SGS), which is then converted to biologically active sulforaphane by an enzyme called myrosinase. Myrosinase is released when the plant is chewed or processed or produced in the gut by bacteria.¹⁹ See Figure 2 for a diagram of sulforaphane breakdown. Unfortunately, cooking partially destroys this enzyme,  limiting sulforaphane production. Glucoraphanin is abundant in broccoli, cauliflower, cabbage, and kale, with the highest concentration found in broccoli and broccoli sprouts.¹⁹ Studies show that just 1 cup of raw broccoli sprouts contains enough sulforaphane (200 µmol) to penetrate breast tissue and stop cancer growth.²³

Indole-3-Carbinol (I3C)

I3C is another compound found in the cruciferous vegetable family, which has an impact on estrogen levels and breast cancer risk. Like sulforaphane, I3C possesses multiple anti-cancer mechanisms including the up- regulation of detoxification enzymes and increasing the 2-OHE1 form of estrogen in the liver.⁵ In controlled clinical trials, oral supplementation with 300–400 mg/ day of I3C has consistently increased urinary 2-OHE1 levels and urinary 2-OHE1:16α-OHE1 ratios in women.^24,25 I3C supplementation also reversed a form of early cervical cancer after just 12 weeks of supplementation.²⁶

Once I3C is ingested it forms  several metabolites, but  the  majority is converted to diindolylmethane (DIM), which is considered the most active metabolite. Like I3C, DIM has also demonstrated an improvement in estrogen metabolism, however it does not have the same volume of clinical research as I3C does. A number of cell studies have shown that it  prevents  the growth of breast cancer cells.

Supplementation with 108 mg/day of DIM also increased urinary 2-OHE1 levels in postmenopausal women suggesting that is has a positive effect on estrogen balance.²⁷ One advantage DIM has over I3C is that it is a more stable molecule which leads to enhanced biological activity.²⁸

Essential Fatty Acids

The omega-3  and  omega-6  class  of polyunsaturated  fatty  acids  exert  a modulating action on estrogen metabolism. High intake of omega-6 fatty acids – linoleic acid (LA) and arachidonic acid (AA) –  interferes with the detoxification of estrogens. Omega-3 fatty acids refer to a group  of three fats: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Hydroxylation is an important biochemical process necessary for detoxification. EPA has been shown to increase 2-hydroxylation of E2 at the expense of C-16α hydroxylation, while DHA decreases the binding of estrogens to the ERs.

Dietary Fibers

Dietary fibers are parts of a plant that do not break down in our stomach, and pass through our system undigested. Soluble fibers dissolve in water, while insoluble fibers do not. Insoluble fibers such as lignins are found in flaxseeds and in the bran layer of grains, beans, and seeds. Fruits and vegetables provide most of the soluble fibers. Both types of fibers are equally important for health, digestion, and preventing various diseases. Soluble fibers are readily fermented in the colon into gases and physiologically active byproducts, while insoluble fibers increase bulk, soften stool, and shorten transit time through the intestinal tract.

Recent studies demonstrate that 16α-OHE1 levels are  affected  by  fiber intake. Soluble fibers favorably modulate the 2/16α ratio while insoluble fibers sequester endogenous estrogens within the gut, decreasing their circulation within the body, their resulting availability to target tissues, and improving their elimination via feces. Current recommendations from the United States National Academy of Sciences, Institute of Medicine suggest that adults consume 20–35 grams of dietary fibers per day, but the average American’s daily intake of  dietary fiber averages only 12–18 grams. Partially hydrolyzed guar gum (PHGG) constitutes an excellent way to increase soluble fibers in your diet, and a good alternative to other highly allergenic alternatives such as wheat fibers or corn- based products. This tasteless, odourless supplement dissolves completely in water and it has been better tolerated and preferred by patients in clinical trials.

B vitamins

The important role of vitamins B6, B12, and folate as cofactors for enzymes involved in the methylation of catechol estrogens (2-OHE1 and 4-OHE1) to less harmful metabolites has already been mentioned.  However,  obtaining B vitamins solely from the diet can represent quite a challenge, especially for the increasing number of individuals adhering to a gluten-free diet. A significant portion of the population presents single nucleotide genetic polymorphisms (SNPs) which interfere with their ability to metabolize certain vitamins to their active form utilized by thebody. For example, it is estimated that between 10 and 15% of North American Caucasians, and >25% of Hispanics present a polymorphism affecting 5,10-methylenetetrahydrofolate reductase (MTHFR), the enzyme needed for the conversion of folic acid to 5-methyltetrahydrofolate (5-MTHF), the primary circulatory form of folate. Since SNPs can affect any other enzymes involved in the metabolism of vitamins, choosing a nutritional supplement containing the metabolically active form of folate (5-MTHF) and other B vitamins (P-5-P, methylcobalamin, etc.) will help ensure that you obtain adequate levels of these crucial nutrients.

Green Tea

Green tea has a large range of potential anti-cancer actions including reducing the growth of cancer cells and the blood vessels that feed them. For   a more detailed discussion on  green tea and cancer please see the article in Advances: Cancer. A recent study added another benefit to the long list when it found that green tea actually blocked breast cancer growth  associated with a powerful xenoestrogen called PhIP (found in grilled or fried meats).²⁹ This is so important because xenoestrogens may be responsible for up to 85% of spontaneous breast cancers.²⁹

Glucaric Acid

Glucaric acid is found in  many fruits and vegetables, with the highest concentrations in oranges, apples, grapefruit, and cruciferous vegetables. Oral supplementation of calcium- D-glucarate (a salt form of glucaric acid) has been shown to inhibit, an enzyme produced by gut bacteria that prevents phase II liver detoxification.30 Elevated beta- glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers.³⁰ Calcium-D-glucarate’s inhibition of beta-glucuronidase activity allows the body to excrete hormones such as estrogen before they can become reabsorbed. support of this action, supplementation with calcium-D-glucarate has been shown to lower serum estrogen levels in rats by 23 percent.³¹

Pulling it all together

There is little doubt that estrogen plays a large role in breast cancer development and growth. Certain forms of estrogen normally produced in the body or found in the environment have  been  linked to higher breast cancer risk. Increasing elimination  and   lowering   exposure to these forms should be a  primary goal in reducing risk and achieving healthy estrogen balance. Various natural substances found in plants and vegetables can promote healthy estrogen balance by binding estrogen receptors and increasing the elimination of excess estrogen. Cruciferous vegetables, organic soy products and green/white tea stand out in the research as the most beneficial. Incorporating these foods into your diet can help to promote healthy estrogen balance and to help reduce breast cancer risk.

REFERENCE

1. “World Cancer Report”. International Agency for Research on Cancer. 2008. Retrieved 2013-07-20.

2. Feigelson H and Henderson B. Review Estrogens and breast cancer. Carcinogenesis. 1996; 17(11):2279-84.

3. Russo J and Russo I. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol. 2006;102(1-5):89-96.

4. Kaur A and Dean C. The Complete Natural Medicine Guide to Women’s Health. Robert Rose inc. Toronto, 2002.

5. Lord R et al. Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. Altern Med Rev. 2002;7(2):112-29.

6. Dallal C and Taioli E. Urinary 2/16 estrogen metabolite ratio levels in healthy women: a review of the literature. Mutat Res. 2010;705(2):154-62

7. Obi N et al. Estrogen metabolite ratio: Is the 2-hydroxyestrone to 16α-hydroxyestrone ratio predictive for breast cancer? Int J Womens Health. 2011;3:37-51.

8. Brody J and Rudel R. Review Environmental pollutants and breast cancer. Environ Health Perspect. 2003; 111(8):1007-19.

9. Fucic A et al. Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain. Environ Health. 2012;11 Suppl 1:S8.

10. Fernandez S and Russo J. Estrogen and xenoestrogens in breast cancer. Toxicol Pathol. 2010;38(1):110-22.

11. Rohrmann S et al. Dietary intake of meat and meat-derived heterocyclic aromatic amines and their correlation with DNA adducts in female breast tissue. Mutagenesis. 2009;24(2):127-32.

12. McKinney N Naturopathic Oncology. An encyclopedic guide for patients & physicians. 2nd edition. Liasion Press: Vancouver; 2012.

13. Turner J et al Molecular aspects of phytoestrogen selective binding at estrogen receptors. J Pharm Sci. 2007;96 (8): 1879–1885.

14. Bennion B et al. PhIP carcinogenicity in breast cancer: computational and experimental evidence for competitive interactions with human estrogen receptor. Chem Res Toxicol. 2005; 8(10):1528-36.

15. Kazor T. The Effects of Soy Consumption on Breast Cancer Prognosis: A review of the literature. The Natural Medicine Journal. 2012.

16. Jackson R et al. Emerging evidence of the health benefits of S-equol, an estrogen receptor β agonist. Nutr Rev. 2011;69(8):432-48.

17. Charalambous C et al. Equol enhances tamoxifen’s anti-tumor activity by induction of caspase-mediated apoptosis in MCF-7 breast cancer cells. BMC Cancer. 2013;13:238.

18. Ho G et al. Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singapore. 1998;27:294–9.

19. Sulforaphane Glucosinolate Monograph. Altern Med Rev 2012;15(4):  352-360.

20. Fahey J and Talalay P. Antioxidant functions of sulforaphane: a potent inducer of phase II detoxifi- cation enzymes. Food Chem Toxicol 1999;37:973-97.

21. Clarke J et al. Multi-targeted prevention of cancer by sulforaphane. Cancer Lett. 2008;269(2):291-304.

22. Li Y et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010;16(9):2580- 90.

23. Cornblatt B et al. Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis. 2007;28:1485-1490.

24. Higdon J et al. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224- 36.

25. Michnovicz J and Bradlow H. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst.1990;82:947-949.

26. Bell M et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 2000;78(2):123-9.

27. Dalessandri K et al. Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004; 50(2):161-7.

28. Bradlow H Review. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In Vivo. 2008;22(4):441-5.

29. Choudhary S et al. Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Carcinogenesis. 2012;33(4):876-85.

30. Calcium-D-glucarate. Altern Med Rev. 2002;7(4):336-9.

31. Walaszek M et al. Dietary glucarate as anti-promoter of 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis. Carcinogenesis 1986;7:1463-1466.