Download Phytoestrogens and Prostate Cancer

Running head: PHYTOESTROGENS AND CANCER
Phytoestrogens, Coumestrol, Resveratrol, and Xenoestrogens Interactions With Cancer
Michaela M. Phillips
Russell Sage College
Author note
Michaela M. Phillips, Department of Nutrition, Russell Sage College
Correspondence concerning this paper should be addressed to Michaela M. Phillips,
Nutrition Department, Russell Sage College, Ackerman Hall, 65 1st Street, Troy, NY, 12180.
Contact: [email protected]
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PHYTOESTROGENS AND THEIR EFFECT ON CANCER
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Abstract
Phytoestrogens in the diet may have an impact on a number of cancers to include ovarian,
prostate and breast cancer. Although studies have shown that soy phytoestrogens decreased
methylation in prostate cancer cell lines treated with genistein and daidzen, the same was not
evident in breast cancer and further investigation of the mechanisms is required before
recommending soy for prevention or treatment. Resveratrol, a compound derived from red wine
that has estrogenic activity, does show promise in the treatment of Estrogen Receptor (ER)
positive breast cancer and should be studied for other cancer cell lines as well. The exact
mechanism of action for resveratrol is unclear. Diet manipulation to include consumption of
cruciferous vegetables, flax seed (lignans), and essential fatty acids promotes hydroxylation of
estrogen metabolites at the -2 position which is chemopreventive. Minimizing exposure to
environmental xenoestrogens such as Bisphenol A is recommended as these have been shown to
promote cancer cell growth in the human breast. Minimizing exposure to xenoestrogens and
ensuring a healthful diet seem to be prime factors in cancer risk reduction. Early adoption of a
healthful diet has been shown to have an impact in later life.
Keywords: Cancer, Phytoestrogen, Isoflavone, Genistein, Daidzen, Coumestrol,
Resveratrol, Lignan, Glycitein
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Introduction
According to the National Cancer Institute’s 2011-2012 Cancer Trends Progress Report,
while other cancer mortality rates are increasing, prostate, breast, lung and colorectal cancer rates
(four most common causes of death from cancer) are falling
(http://progressreport.cancer.gov/highlights.asp). Any cancer diagnosis is one too many and
measures should be found to eradicate cancer. This paper evaluates the current research on
ovarian, prostate and breast cancer, to determine if phytoestrogens or certain estrogenic
compounds impact the cancer. Specific phytoestrogens such as isoflavones (daidzen, genistein),
glycitein, lignans, will be analyzed. In addition coumestrol, resveratrol, and xenoestrogens will
be examined.
Metabolism of Estrogen
On average, women produce a few hundred micrograms of estradiol per day (Lord &
Bongiovanni, 2002, p114). Most of the estradiol is converted into estrone and estriol (Lord &
Bongiovanni, 2002, p114). These products are oxidized by isoenzymes of cytochrome P450 and
hydroxylated at the -2, -4, or -16 positions (Lord & Bongiovanni, 2002, p114). CYP1A1 is the
enzyme that catalyzes the reaction at the -2 position whereas CYP1B1 catalyzes the reaction at
the -16 position (Lord & Bongiovanni, 2002, p114). CYP1A1 is inducible by diet manipulation
whereas CYP1B1 is not (Lord & Bongiovanni, 2002, p114). Methylation and Glucuronidation
occur prior to excretion into the urine or uptake as bile (Lord & Bongiovanni, 2002, p115).
Estrogen metabolites include 2-OHE1 (Hydroxyestrone), 2-OHE2 (Hydroxyestradiol), 4OHE1, 4-OHE2, and 16-OHE1 (Lord & Bongiovanni, 2002, p115). The 2 Hydroxy products
do not cause cell proliferation compared to the 16 and the 4 hydroxy products.
PHYTOESTROGENS AND THEIR EFFECT ON CANCER
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Many factors, to include environment and diet, can affect estrogen metabolism. In 2002,
the Alternative Medicine Review Journal published a review of estrogen metabolism with regard
to cancer causation and explored ways to increase cytochrome P450 isozyme hydroxylation at
the number 2 vice the number 16 position of E2 or estradiol (Lord & Bongiovanni, 2002, p114).
They claim that the higher the -2 to -16 hydroxylation ratio, the less the risk of developing cancer
and that we can induce more -2 hydroxylation by manipulating the diet (Lord & Bongiovanni,
2002, p114). Specifically, cruciferous vegetables, Omega-3 fatty acids and lignans are
favorable to promote estrogen metabolism and promote hydroxylation to the -2 position by
induction of the CYPA1 enzyme (p112). Although not statistically significant, a study of over
5000 women 35 and older who were followed for 9.5 years indicated that those in the top third
highest ratios of -2/-16 hydroxyestrone1 had lower risks for breast cancer (Lord & Bongiovanni,
2002, p115). In the same study, postmenopausal women with 15% lower ratios compared to
control subjects developed breast cancer. This result was significant (Lord & Bongiovanni,
2002, p116). Another study of 10,876 Italian women between the ages of 35 and 69 were
followed for 5.5 years. Results from this study showed that subjects with lower -2/-16 ratios had
reduced risk of developing cancer (Lord & Bongiovanni, 2002, p116).
Dietary factors that increase 2-OHE products include cruciferous vegetables, essential
fatty acids, flax, and soy, although soy has varied effects and cannot be definitively used to
reduce cancer risk (Lord & Bongiovanni, 2001, p123).
Phytoestrogens and Ovarian Cancer
Ovarian cancer risk has not been studied as extensively as other types of cancer such as
breast cancer. Risk factors have not been clearly identified, but parity and tubal ligation have
PHYTOESTROGENS AND THEIR EFFECT ON CANCER
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been shown to be protective (Bandera, 2011, p3). According to the American Cancer Society
(ACS), only 10% of ovarian cancers are inherited through genes (American Cancer Society,
2013). Bandera (2011) studied the effects of phytoestrogens on epithelial ovarian cancer,
specifically total phytoestrogens, isoflavones, lignans, and coumestrol in supplements and food.
Two hundred and five cases of ovarian cancers were randomly selected from six counties in New
Jersey from the state cancer registry. Three hundred and ninety controls were selected by
random digit dialing from the Centers for Medicare and Medicaid Service (CMS) listing
(Bandera, 2011, p2).
Diet information was collected using a modified Block Food Frequency Questionnaire
(Bandera, 2011, p2). Lignans which are found in flaxseed, grain/bread, nuts, coffee, tea, fruits
and vegetables, are the major source of phytoestrogens within the study population (Bandera et
Al., 2011, p2).
The study showed little evidence that isoflavones or lignans were associated with decreased
risk (OR for highest vs. lowest tertile of lignan intake = 1.0, 95% CI: 0.68-1.79) and there was
no evidence showing coumestrol had any association (Data was not shown). Total phytoestrogen
consumption likewise suggested little evidence to indicate association with decreased cancer risk
(Bandera et All, 2011, p5).
Although the consumption of phytoestrogens did not show any statistically significant effect
on ovarian cancer as evidenced by an OR of 0.66 for the highest tertile (CI of 95%: 0.41-1.08),
the authors still claim that consumption of phytoestrogens in food might decrease the risk of
ovarian cancer based on the literature review (Bandera et Al, 2011, p7-8).
PHYTOESTROGENS AND THEIR EFFECT ON CANCER
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Phytoestrogens and Prostate Cancer
Because prostate cancer is the leading cause of cancer death in males (Adjakly et Al.,
2001), a dietary solution could be extremely beneficial. Adjakly et Al. explored whether soy
isoflavones, specifically daidzein and genistein have any effect on prostate cancer lines.
Through methylation dependent digestion and qPCR analysis, Adjakly et Al. found that
the two soy phytoestrogens, daidzen and genistein, reversed hypermethylation of the BRCA1,
EPHB2, and GSTP1 genes in the DU-145 and PC-3 cell lines, thus should regain oncosuppressor
functionality (Adjakly et Al., 2011).
Through western blot analysis, Adjakly et Al. found that treatment with genistein and
daizen upregulated proteins for BRCA1, EPHB2, and GSTP1 in small amounts. They claim that
a longer exposure time to the treatment may have resulted in greater amount of protein
expression (Adjakly et Al., 2011).
In summary, soy phytoestrogens have been shown to reverse DNA methylation similar to
prostate cancer drug 5-acytidine, but further research involving animal studies and tissue
biopsies would be needed to confirm this (Adjakly et Al., 2011).
Phytoestrogens and Breast Cancer
Soy Isoflavones. The American Cancer society sees no harmful effects of soy consumption
(American Cancer Society, 2013). Sakamoto et Al. (2009), in a study of dietary phytoestrogen
effects on estrogen receptor positive breast cancer cells, found that soy phytoestrogens
moderately increased cancer cell growth in the presence of E2 (17-estradiol). Daidzen and
genistein did not reduce tumor activity and only slightly suppressed the effects of E2. Genistein
also induced apoptosis and reduced the Bcl-2/Bax ratio. Glycitein repressed cell growth,
PHYTOESTROGENS AND THEIR EFFECT ON CANCER
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induced apoptosis and slightly reduced Bcl-2/Bax ratio but had a weak effect on ER
transactivation compared with other phytoestrogens. In the colony formation assay, glycitein
was shown to reduce the number of colonies by 38%. Sakamoto et Al. (2009) conclude against
utilizing soy isoflavones for breast cancer or as HRT in postmenopausal women.
Resveratrol. Sakamoto et Al. (2009) conducted experiments in both low and normal doses of
resveratrol in blood serum and found this estrogenic compound promising as it inhibited E2 and
showed the greatest antitumor effect whether or not E2 was present (p858). In the colonie
forming experiment with 10-8 M E2 concentration, resveratrol reduced the number of colonies
by 30% (p858). The exact mechanisms of action could be clarified in future research.
Coumestrol. Coumestrol is found in alfalfa, red clover, legumes, and soy products. Sakamoto
et Al. (2009) found that coumestrol stimulates tumor growth, but is found in such low
concentrations in food that it is unlikely to increase the risk of developing breast cancer.
Xenoestrogens. This category of compounds includes chemicals that have estrogenic properties
such as Bisphenol A (BPA) that can leach out of plastic when heat is applied. In July 2013, the
FDA banned the use of BPA in infant formula packaging due to market abandonment, not safety
(http://www.fda.gov/food/newsevents/constituentupdates/ucm360147.htm); however, the
European Union and Canada have banned the use of BPA in baby bottles
(http://www.efsa.europa.eu/en/topics/topic/bisphenol.htm). Fernandez and Russo (2010)
demonstrated in their research that xenoestrogens such as bisphenol A could be involved in the
initiation or progression of breast cancer. In their review of estrogen metabolism and cancer,
Lord and Bongiovanni found that limiting xenoestrogen exposure lowers cancer risk possibly by
reducing 16hydroxyllation (2002, p114).
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Conclusion
This paper examined phytoestrogens and estrogenic compound impact on cancer
initiation, promotion and progression. Because cancer is one of the leading causes of death
worldwide, it would be beneficial to have a treatment with no or minimal side effects that would
cause cancer cell death or apoptosis and increase the effect of oncosuppressor genes.
Overall, increased ratios of -2 to -16 OHE seemed beneficial to prevent initiation of
cancer cells. Increasing hydroxylation at the -2 position can be induced through the diet,
specifically through consumption of cruciferous vegetables, flax, and essential fatty acids.
Increasing -2 hydroxylation can be chemo-preventive (Lord and Bongiovanni, 2011).
Soy isoflavones reversed DNA methyllation in prostate cancer cell lines but did not
reduce tumor activity in breast cancer cells. Glycitein repressed tumor growth and induced
apoptosis, but had a weak effect on estrogen receptor transactivity (Sakamoto et Al., 2009). In
the Shanghai Breast Cancer Survival Study, women in the highest quartile of soy intake showed
decreased mortality (HR 0.67, 95% CI, 0.51-0.88) and recurrence (HR 0.66, 95% CI, 0.52-0.84)
compared with the lowest quartile (Shu et Al., pg 1). The type of soy product consumed in
Shanghai may be different than soy consumed in the US. Further investigation is needed before
soy can be recommended for reduction of all cancer risk.
Xenoestrogens could be involved in initiation and progression of cancer, but further
research is necessary. Further research could also focus on the mechanism by which resveratrol
reduces cancer risk and whether it can also be used to inhibit or cause apoptosis in all cancer cell
lines. Glycitein may also need further study at higher doses to determine its effect on cancer
cells at varied doses.
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