Phytoestrogens and Breast Health

In the quest to identify nutritional compounds that potentially influence breast cancer (and other hormonally driven cancers), phytoestrogens are among the best researched. The label “phytoestrogen” has been given to specific compounds in plants and foods that under certain conditions appear to have a modulatory effect on estrogen and other hormone receptors.

Plants contain a diversity of beneficial compounds, including a wide range of phenolic compounds, flavonoids, lignans, and phytosterols. Each phytochemical exerts multiple actions, both alone and in combination within and on target cells, including the epigenome. Abundant data indicates that these compounds act on estrogen receptors; for example, isoflavone and other compounds referred to as phytoestrogens have an ability to inhibit local estrogen synthesis and induce epigenetic changes.¹ According to the most recent literature, phytoestrogens have demonstrated positive effects on breast cancer prognosis, including breast cancer recurrence and mortality in survivors of the disease.²

One proposed mechanism as to how phytoestrogenic herbs potentially inhibit breast cancer and work synergistically with the chemotherapeutic drugs Afinitor (Everolimus) and Aromasin is through receptor binding antagonism. Phytoestrogenic compounds may act as extremely weak estrogens that bind to the ER receptors ERalpha and ERbeta. The action is not strong enough to induce proliferative effects, but sufficient to inhibit the binding of endogenous estrogens and xenoestrogens that might otherwise induce breast cancer cell proliferation.³

Likewise, purported phytoestrogenic herbs appear to demonstrate pleiotrophic effects and inhibit breast cancer by modulating or down-regulating breast cancer stem cell proliferation through various pathways including Hedgehog and Wnt inhibition. They likely reduce pro-inflammatory cytokines at various pathways including NF-kB, COX-2, LOX-5, IL-6, inhibit HDAC, gene mutations in breast cancer including p53, PTEN, Bcl-2, p27, p21, myc signaling, control growth factors such as insulin-glucose, PI3-K, mTOR, EGFR, VEGF pathways, and assist in the removal of cancer promoting toxins through pathways such as Nrf-2 up-regulation. The following diagram demonstrates the proposed interface of phytoestrogens and human physiology.

Many natural compounds referred to as phytoestrogens are absorbed and conjugate to glucuronic acid and to a lesser extent sulphuric acid in the hepatic circulation. They are then de-conjugated prior to excretion with urinary concentrations increasing parallel to consumption.⁶ There are generally very low levels of biologically active ‘free’ unconjugated phytoestrogens in the circulation (< 3% of the total) and blood levels are in the ng/mL range or lower.⁷ One may then argue the relevance of in vitro studies or studies that inject large amount of isolated compounds into animals.

Phytoestrogens alter gene transcription by:

(1) Acting as estrogen modulators, being agonist/antagonists binding to the estrogen receptors;

(2) “Modulating cell signaling pathways… activated by cell surface oestrogen receptors or growth factor receptors and ultimately activate gene transcription by activating oestrogen receptors or other transcription factors (TF);

(3) Inhibiting /stimulating transcription of genes regulating apoptosis and the cell cycle;

(4) Epigenetic alterations in DNA, histone proteins and RNA to alter transcription/translation of proteins.”⁸

For example, one study showed that µmol/L doses of genistein and diadzein (phytoestrogens) “might reverse” DNA hypermethylation in breast cancer cells thus restoring expression of the oncosuppressor genes BRCA1 and BRCA2.⁹ Furthermore, epidemiological evidence strongly suggests a geographical basis for the reduced incidence of many hormone-related cancers, such as breast and prostate. Reduced incidence of hormone-related cancers has been correlated to local diets rich in isoflavones.^10-12

According to the results of a study presented at the AACR 102nd Annual Meeting 2011, women with the highest intake of soy food (categorized as more than 23 mg isoflavones per day) had a nine percent reduced risk of mortality and a fifteen percent reduced risk for recurrence, compared to those with the lowest intake. There was also no increase in risk for cancer recurrence or death among survivors of breast cancer with soy food consumption.¹³

My conclusion is that fermented soy foods (not soy supplements) offer the potential benefit of added protection against breast cancer and even possible suppression of breast cancer. Classic examples of traditional soy foods (which differ from commercial soy foods and isolates) include miso, tofu, tempeh, and natto, all of which contain isoflavones such as genistein.

A recent systematic review (2013) reviewed 127 articles on soy and 4 articles on red clover. Research on “human intervention or observational data pertaining to the safety and efficacy of soy and red clover isoflavones in patients with or at risk of breast cancer ” were reviewed. The conclusion of this study found that “soy does not have estrogenic effects in humans. Soy intake consistent with a traditional Japanese diet appears safe for breast cancer survivors”, and soy consumption, based on traditional foods, may be associated with reduced risk of breast cancer incidence, recurrence, and mortality.¹⁴

In a 2013 meta-analysis of eight studies investigating the effect of soy consumption on the prognosis of patients with breast cancer, the researchers found “high soy intake was signifıcantly inversely associated with overall mortality and recurrence; results were signifıcant in postmenopausal women but not in premenopausal women.” ¹⁵

I feel confident that phytoestrogens, when used in the form of whole plant extract supplements and foods, pose little risk. In fact, they may provide modest cancer suppressing effects as well as synergistic effects when used with chemotherapeutic drugs. Likewise, there may likely be protective effects. These conclusions are based on animal models, human trials, and epidemiological research. In next week’s post, I’ll discuss the botanicals that are often referred to as phytoestrogens, and the research that supports their benefits.

References:

1. Bilal I, Chowdhury A, et al. Phytoestrogens and prevention of breast cancer: The contentious debate, World J Clin Oncol. 2014 Oct 10;5(4):705-12. doi: 10.5306/wjco.v5.i4.705.
2. Alipour S, Jafari-Adli S, et al. Benefits and harms of phytoestrogen consumption in breast cancer survivors, Asian Pac J Cancer Prev. 2015;16(8):3091-396.
3. Kuiper G, Lemmen J, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology, 1998, 139(10), 4252-4263.
4. Albini A, Rosano C, et al. Phytoestrogens and Endocrine Disruptors in Breast Cancer, Current Medicinal Chemistry, 2014, Vol. 21, No. 9 1141
5. Bilal I, Chowdhury A, et al. Phytoestrogens and prevention of breast cancer: The contentious debate, World J Clin Oncol.2014 October 10; 5(4): 705-712. Published online 2014 October 10. doi: 10.5306/wjco.v5.i4.705.
6. Karr S, Lampe J, et al. Urinary isoflavonoid excretion in humans is dose dependent at low to moderate levels of soy-protein consumption. Am J Clin Nutr 1997; 66: 46-51
7. Patisaul H, Jefferson W. The pros and cons of phytoestrogens. Front Neuroendocrinol 2010; 31: 400-419; Verkasalo PK, Appleby PN, Allen NE, Davey G, Adlercreutz H, Key TJ. Soya intake and plasma concentrations of daidzein and genistein: validity of dietary assessment among eighty British women (Oxford arm of the European Prospective Investigation into Cancer and Nutrition). Br J Nutr 2001; 86: 415-421.
8. Bilal I, Chowdhury, A et al. Phytoestrogens and prevention of breast cancer: The contentious debate, World J Clin Oncol.2014 October 10; 5(4): 705-712. Published online 2014 October 10. doi: 10.5306/wjco.v5.i4.705.
9. Bosviel R, Dumollard E, et al. Can soy phytoestrogens decrease DNA methylation in BRCA1 and BRCA2 oncosuppressor genes in breast cancer? OMICS. 2012;16:235-244.
10. Messina M, Abrams DI, Hardy M. Can clinicians now assure their breast cancer patients that soyfoods are safe? Womens Health (Lond Engl). 2010 May;6(3):335-8. doi: 10.2217/whe.10.20;
11. Messina M, Wood C. Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary, Nutrition Journal 2008, 7:17 doi:10.1186/1475-2891-7-17;
12. Messina M, Messina V, Jenkins DJ. Can breast cancer patients use soyafoods to help reduce risk of CHD? Br J Nutr. 2012 Sep;108(5):810-9. Epub 2012 Jul 3.
13. Shu, X.oO., Soy Isoflavones Not A Risk For Breast Cancer Survivors, April, 2011, American Association for Cancer Research (AACR).
14. Fritz H, Seeley D, et al. Soy, red clover, and isoflavones and breast cancer: a systematic review, PLoS One. 2013 Nov 28;8(11):e81968. doi: 10.1371/journal.pone.0081968. eCollection 2013.
15. Anna H. Wu, Eunjung Lee, and Cheryl Vigen. Soy Isoflavones and Breast Cancer, 2013 ASCO EDUCATIONAL BOOK |asco.org/edbook] pg. 103-104.