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Do Phytoestrogens Promote Cancer Growth?

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Phytoestrogens are plant generated estrogen-like compounds that possess the ability to modulate hormone activity within the human body.

In the scientific and medical community, there is a great deal of controversy surrounding the intake of phytoestrogens. Despite decades of research, there is a rough consensus on whether phytoestrogens are beneficial or harmful to human health.

While most individuals equate phytoestrogens with soy, phytoestrogens exist rather ubiquitously through the plant world.

Foods or plant matter highest in phytoestrogens are1:

-Nuts
-Oilseeds (sunflower, canola, etc.)
-Soy and soy products
-Flaxseed
-Legumes
-Wheat and wheat products
-Processed meat products

There are four main classifications for dietary phytoestrogens2:

(The listing of examples in each category is not exhaustive)

1) Flavonoids:
-flavonols (quercetin, kaempferol, myricetin, fisetin, pachypodol, rhamnazin)
-flavones (apigenin, luteolin, tangeritin)
-flavanones (epicatechin, eriodictyol, hesperetin, homoeriodictyol, naringenin)
-isoflavonoids (glycitein, genistein, daidzein, formononetin, Biochanin A)
-antocyanidins
-catechins (proanthocyanides)
-prenylflavonoids (6‐prenylnaringenin, 6‐geranylnaringenin, 8‐prenylnaringenin and isoxanthohumol)

2) Lignans:
-secoisolariciresinol
-matairesinol
-pinoresinol
-lariciresinol

3) Coumenstans:
-coumestrol

4) Stilbenes (polyphenols):
-Resveratrol
-Phytoalexins

The most commonly consumed and researched forms of phytoestrogens in the western diet are1: 

-Isoflavones (genistein, daidzein, glycitein, formononetin)
-Lignans (secoisolariciresinol, matairesinol, pinoresinol, lariciresinol)
-Coumestan (coumestrol)

Historically, we see the most considerable consumption of phytoestrogens in Asian countries. Intake of phytoestrogens through soy foods across Asia is found most frequently in edamame, tofu, fermented soy, bean curd, and soy sauces. Isoflavones in soy occur in glycoside form and break down into aglycone form during digestion. Bacterial hydrolysis to aglycone metabolites also takes place during the fermentation of soy.

While Asians consume less processed soy, Western consumption of soy tends towards more processing seen in bars, dietary supplements, food additives, and infant formulas.

Prominent research areas surrounding phytoestrogens include bone health, menopause, cancer, cardiovascular health, infant health, and cognitive function. Much of the data on soy remains inconclusive.

To determine why phytoestrogens generate such wide-ranging outcomes, we first need to understand the nature of their biological activity.

STRUCTURE AND BIOLOGICAL CONSEQUENCES

Phytoestrogens carry a structural similarity to 17-β-oestradiol (E2), which is considered the most potent of the three natural estrogens. By resembling E2, phytoestrogens act as competition for estrogen receptor site binding. Binding at the receptor results in modulation of receptor site expression and is considered the primary mode of action for phytoestrogens. When a phytoestrogen binds at an estrogen receptor site, it outcompetes the binding of endogenous estrogens. Phytoestrogens are considered weaker estrogens. The result of binding by phytoestrogens is deemed to be primarily anti(oestrogenic)3.

All humans have two primary estrogen receptors types: ERα and ERβ.

When phytoestrogens bind to ERα, we observe the proliferation of estrogen-dependent cancers, while the activation of ERβ can counteract ERα stimulation. Human tissues all contain various concentrations of each type of estrogen receptor throughout the body. Differential receptor expression suggests the hormonally regulated activity of the organ is unique at each location.

Research comparing 17-β-oestradiol (E2) vs. various phytoestrogens reveals most phytoestrogen compounds prefer binding to ERβ receptor sites.3

A study on the soy-derived isoflavone genistein reveals activation of ERβ at much lower concentrations before ERα activation occurs.4 A preference for ERβ is considered protective from an oncogenic standpoint.

HUMAN VARIABILITY AND PHYTOESTROGENS

New and emerging research is seeking to investigate the inter-individual variations which account for the lack of conclusive data on phytoestrogens.

Owing to research in the following areas, we now have a more accurate depiction of the influence of phytoestrogens on human physiology: 

-The influence of phytoestrogens on genes which regulate cell proliferation and differentiation
-Cross-cultural variability in response to phytoestrogens
-Variation in estrogen receptor expression
-Gut microbiota and their impact on the metabolism of phytoestrogens
-Age-related epigenetic modifications in response to the consumption of phytoestrogens
-How differences in breast cancer types may respond to the intake of phytoestrogens

An ever-expanding body of research supports the contention that our lifestyle and environmental factors heavily influence our genome’s expression. In research involving phytoestrogens and cancer development, there is an added focus on studying cell-mediated interactions affecting apoptosis, cell proliferation and survival, inhibition of angiogenesis and metastasis, and antioxidant properties of phytoestrogens. Dangers attributed to soy intake stem from potential implications in the progression of cancer development.

All studies to date have been performed in vitro, in animal models, or gathered through epidemiological data.

The following is a summary of key findings on the proposed safety and biological activity of soy:

  1. Epidemiological data suggest an inverse association between soy consumption and breast cancer risk in Asian women who consume soy as part of their traditional diet.5,6 Asian women, who migrate to North America or Europe and consume westernized foods, see an increase in breast cancer incidence.7
  2. Genistein and daidzein, two of the primary isoflavones found in soy, have shown in vitro to reverse hypermethylation-induced inactivation of tumor suppressor genes. These phytoestrogen derivatives are considered possible agents for cancer therapy by correcting for healthy gene expression of tumor suppressor genes.8
  3. Isoflavones display a potent ability to down-regulate key enzymes involved in cell proliferation and transformation.9, 10, 11 Specific inhibition of enzymes such as tyrosine specific protein kinase, mitogen-activated kinase, and DNA topoisomerase II suggest additional benefits of isoflavones in cancer treatment.
  4. According to the American Society of Clinical Oncology, 60-75% of all diagnosed breast cancer cases are estrogen receptor-positive, and 65% of these cases are also progesterone receptor-positive.12 Until recently, scientists believed that phytoestrogens’ activity occurred only at estrogen receptor sites due to their conformational similarity to 17-β-oestradiol. Newer evidence suggests isoflavones are also able to reduce the activity of estrogen receptor-negative breast cancer tissue.13, 14 The action of phytoestrogens likely includes additional cellular mechanisms that go beyond binding at estrogen receptor sites.
  5. In vitro studies that review the binding capacity for isoflavones show an affinity for ERβ receptors. In cancer types such as advanced lobular or high-grade ductal carcinomas when there is a loss of ERβ expression, the use of isoflavones in the management of cancer progression is questionable.15
  6. Inter-individual differences in the metabolism of ligands and flavonoids may account for some of the observed biological activity variances. Interestingly, it appears that not everyone is capable of metabolizing ligands and flavonoids to their final products. Ligands, found in flaxseeds, grains, and berries, can be broken down into the metabolites enterodiol (EDL) and enterolactone (ENL). Isoflavone daidzein can be broken down into the metabolites equol or to O‐desmethylangolensin (O‐DMA). According to an article in the American Journal of Clinical Nutrition, the variability seen in phytoestrogen metabolism is related to gut microbial identity and activity; genetic determinants of biotransformation enzyme expression, stability, and activity; environmental exposures that influence the gut microbes and biotransformation enzymes; and variation in concentrations of endogenous compounds that modulate biotransformation pathways.16 According to the same article, approximately 30-50% of humans have bacteria that produce equol, while 80-90% harbor the bacteria that produce O-DMA. Equol producers are of particular interest because equol production is associated with reduced risk of certain cancers due to heightened estrogen-activity. As of 2019, the understanding of which microbial communities are responsible for equol production appears limited. Microbiota, which generates equol appear most prominently in vegetarians alongside a carbohydrate-rich diet with dairy.17
  7. In tandem with the epidemiological data suggesting soy has favorable considerations for Asian women, it appears timing of exposure to soy relative to cancer formation is another key aspect. During adolescence, soy intake appears to induce changes in gene expression, which may be protective against cancer in later years.18,19,20
  8. Phytoestrogens appear to exhibit bimodal activity on breast cancer tissue in women of different hormonal status. In studies involving rat models, scientists observe bidirectional outcomes on breast cancer cell growth under premenopausal and postmenopausal conditions. These findings on breast cancer growth suggest phytoestrogens’ activity is dependent on the hormonal status of the woman and may be dangerous for postmenopausal women with ER-positive breast cancer.21
  9. The fermentation of soy appears to lead to greater bioavailability of isoflavones. The pathway responsible for this occurs via bacterial hydrolysis of glycosides to aglycone metabolites. Other studies suggest total absorption is still the same.22 Fermentation does not seem to affect Equol production.23 Higher bioavailability of isoflavones raises concerns about whether higher plasma levels of phytoestrogens equates to better health outcomes.
  10. Although phytoestrogens are considered weaker estrogens, their plasma concentrations can be up to three orders of magnitude higher than estradiol after consumption of two servings of soy food.24 The potential as an endocrine-disrupting agent remains high for women with low or very high estradiol status.
  11. A meta-analysis of fifteen placebo-controlled treatment groups and an additional 32 reports involving 36 treatment groups determined there are no significant effects of soy protein or isoflavone intake on testosterone, sex hormone-binding globulin, free testosterone or free androgen index in men.25 The use of soy in men who have prostate cancer remains inconclusive.26,27

Conclusion

Despite extensive inquiry, the research on soy remains heavily convoluted. Individual variability also makes it difficult to predict the relationship between phytoestrogens and cancer development.  The biological activity of phytoestrogens appear to be modulated by age, lifestyle, risk factors, diet, hormones, microbiome, pre-existing conditions, and type or quantity of phytoestrogen consumed.

1. Thompson, LU et al. “Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans, and coumestan.” Nutr Cancer. 2006, 54(2), 184‐201.
2. Patisaul, HB et al. “The pros and cons of phytoestrogens.” Front Neuroendocrinol, 2010 Oct 31(4), 400-419.
3. Rietjens M et al. “The potential health effects of dietary phytoestrogens” British Journal of Pharmacology. 174(11), 2017 June, 1263-1280.
4. Rietjens IM et al. “Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks.” Mol Nutr Food Res, 2013, 57, 100-113.
5. Dong, J.Y.; Qin, L.Q. “Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies.” Breast Cancer Res. Treat, 2011, 125, 315–323.
6. Xie, Q. et. al.” Isoflavone consumption and risk of breast cancer: A dose-response meta-analysis of observational studies.” Asia Pac. J. Clin. Nutr. 22, 2013, 118–127.
7. Deapen, D. et al. “Rapidly rising breast cancer incidence rates among Asian-American women.” J. Cancer, 2002, 99, 747–750.
8. Qin, W et al. “Soy Isoflavones Have an Antiestrogenic Effect and Alter Mammary Promoter Hypermethylation in Healthy Premenopausal Women” Nutr Cancer, 2009, 61(2), 238-244.
9. Akiyama, T. et.al. “Genistein, a specific inhibitor of tyrosine-specific protein kinases.” Biol. Chem. 1987, 262, 5592–5595.
10. Markovits, J. et. Al “Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase ” Cancer Res. 1989, 49, 5111–5117.
11. Pan, H. “Genistein inhibits MDA-MB-231 triple-negative breast cancer cell growth by inhibiting NF-κB activity via the Notch-1 pathway.” J. Mol. Med, 2012, 30, 337–343.
12. Burstein, H.J. et al. “Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American society of clinical oncology clinical practice guideline focused update.” Clin. Oncol. 2014, 32, 2255–2269.
13. Pan, H. et al. “Genistein inhibits MDA-MB-231 triple-negative breast cancer cell growth by inhibiting NF-κB activity via the Notch-1 pathway.” J. Mol. Med. 2012, 30, 337–343.
14. Li, Z. et al. “Genistein induces cell apoptosis in MDA-MB-231breast cancer cells via the mitogen-activated protein kinase pathway.” In Vitro 2008, 22, 1749–1753.
15. Huang, B. et al. “Differential expression of estrogen receptor alpha, beta1, and beta2 in lobular and ductal breast cancer.” Natl. Acad. Sci. USA 2014, 111, 1933–1938.
16. Lampe, Johanna W. “Is equol the key to the efficacy of soy foods?” Am J Clin Nutr, 2009 May, 89(5), 1664-1667.
17. Mayo, B. et al. “Equol: A Bacterial Metabolite from The Daidzein Isoflavone and Its Presumed Beneficial Health Effects.” Nutrients, August 2019, 11(9), 2231.
18. Shu, X et al. “Soyfood Intake During Adolescence and Subsequent Risk of Breast Cancer Among Chinese Women.” Cancer Epidemiol Biomarkers Prev, 2001 May, 10(5), 483-8.
19. Wu, A. H. et al. “Adolescent and Adult Soy Intake and Risk of Breast Cancer in Asian-Americans.” Carcinogenesis, 2002 Sept, 23(9), 1491-6.
20. Korede, L. A. et al. “Childhood Soy Intake and Breast Cancer Risk in Asian American Women.” Cancer Epidemiol Biomarkers Prev, 2009 Apr, 18(4), 1050-9.
21. Ju, Y.H. et al. “Genistein Stimulates Growth of Human Breast Cancer Cells in a Novel, Postmenopausal Animal Model, With Low Plasma Estradiol Concentrations.” Carcinogenesis, 2006 June, 27(6), 1292-9.
22. Zubik, L. and Meydani, M. “Bioavailability of Soybean Isoflavones from Algycone and Glucoside Forms in American Women.” Am J Clin Nutr, 2003 Jun, 77(6), 1459-65.
23. Okabe, Y. et al. “Ingestion of Aglycone-Rich Fermented Soybeans Compared With Glucoside-Rich Non-Fermented Soybeans in Japanese Postmenopausal Women.” J Sci Food Agric, 2011 Mar 15, 91(4), 658-63.
24. Van der Velpen, V.; Hollman, P.C.; van Nielen, M.; Schouten, E.G.; Mensink, M.; Van’t Veer, P.; Geelen, A. Large inter-individual variation in isoflavone plasma concentration limits use of isoflavone intake data for risk assessment. J. Clin. Nutr, 2014, 68, 1141–1147.
25. Hamilton-Reeves, J.M. et al. “ Clinical Studies Show No Effects of Soy Protein or Isoflavones on Reproductive Hormones in Men: Results of a Meta-Analysis.” Fertil Steril, 2010 Aug, 94(3), 997-1007.
26. Jarred R.A. et al. “Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones.” Cancer Epidemiol. Prev.2002, 11, 1689–1696.
27. Hamilton-Reeves J.M. et al. “Short-term soy isoflavone intervention in patients with localized prostate cancer: A randomized, double-blind, placebo-controlled trial.” PLoS ONE,2013 Jul 12, 8(7).

Naomi Sachs, B.Sc., A.C.H.N., PFT

www.naomisachs.com 

Fully-certified since 2015, Naomi has been successfully coaching clients throughout North America and facilitating their self-growth in the nutrition and fitness realm. If you are feeling overwhelmed by the myriad of health strategies available, her services aim to introduce clarity and self-motivation.