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Soy Phytoestrogens -- They Can Actually Promote Cancer!

January 02, 2008 | 17,375 views

Do phytoestrogens prevent cancer?

The evidence to support the industry claim is scant and recent work indicates that phytoestrogens may actually increase the risk of breast cancer. And HOT OFF THE PRESS is an article from Japan in which the author proposes a link between the soy phytoestrogen genistein and infantile leukemia.

Infantile leukemia and soybeans -- a hypothesis [editorial] Abe T.  Leukemia 1999, 13:317-20

Abstract Recent molecular-genetic studies have revealed that in the majority of patients with secondary leukemia induced by topoisomerase II (topo II) inhibitors and also with infantile acute leukemia (IAL), the breakpoints are clustered within scaffold attachment regions (SARs) of 3'-MLL-bcr near exon 9.

Genistein, abundant in soybeans, is reported to be a potent nonintercalative topo II inhibitor. It interferes with the break-reseal reaction of topo II by stabilizing a cleavable complex, which in the presence of detergents, results in DNA strand breaks. The present study revealed that genistein induced chromatid-type aberrations, in which chromatid exchanges are often observed.

Genistein seems to act in a manner very similar to that of VP-16, although the latter is reported to produce both chromatid- and chromosome-type aberrations.

In view of this pharmacological similarity between genistein and VP-16, and also the similarity of breakpoint clustering regions within the MLL gene in reported cases with secondary leukemia and IAL, genistein may be largely responsible for the development of IAL.

Earlier work by Manfred Metzler has already shown that genistein is a potential clastogen; Metzler's work has been reported in the following articles

Genotoxicity of estrogens. Metzler M, Kulling SE, Pfeiffer E and Jacobs E.  Z Lebensm Unters Forsch A 1998, 206: 367-73.

Abstract Genotoxic effects of the endogenous mammalian estrogen 17-beta-estradiol and the synthetic estrogen diethylstilbestrol have recently been demonstrated, e.g. the induction of numerical chromosome aberrations (aneuploidy, i.e. the condition in which on or more whole chromosomes of a normal set are missing or present in more than the usual set of copies) and the formation of deoxyribonucleic acid (DNA) adducts. 

It is likely that the genotoxicity of the estrogens acts in concert with their hormonal activity to give rise to carcinogenic effects.  Many of the phytoestrogens that occur in plants and the numerous anthropogenic estrogens in our environment, which are ingested in food, have not yet been examined for their genotoxic potential.  Recent studies have demonstrated that some but not all of these estrogens exhibit genotoxicity.

The type and strength of the genotoxicity strongly depends on the chemical structure and does not correlate with estrogenicity.  For example, coumestrol and genistein are clastogenic in cultured mammalian cells and lead to gene mutations, whereas biochanin-A and bisphenol-A have the potential to aneuploidy. 

Daidzein, enterolactone, enterodiol and certain bisphenols are devoid of genotoxic effects.  The genotoxicity should be determined individually for each estrogen and taken into account in the assessment of carcinogenic risk.

Induction of micronuclei, DNA strand breaks and HPRT mutations in cultured Chinese hamster V79 cells by the phytoestrogen coumoestrol. Kulling SE, Metzler M.  Food Chem Toxicol 1996, 35:605-13.

Abstract Coumoestrol (COUM), genistein (GEN) and daidzein (DAI) are major phytoestrogens present in numerous plants eaten by humans and food-producing animals. Little is known about the genotoxicity of these natural compounds.

The effects of COUM, GEN and DAI were studied in cultured Chinese hamster V79 cells at various endpoints. None of the substances affected the cytoplasmic microtubule complex or the mitotic spindle.

However, COUM and GEN but not DAI proved to be strong inducers of DNA strand breaks and micronuclei containing acentric fragments, as shown with antikinetochore antibodies. The clastogenicity of GEN may be due to its non-intercalative inhibitory effect on topoisomerase II, whereas COUM may act through topoisomerase II inhibition and/or DNA intercalation.

COUM was also a clear inducer of hypoxanthine guanine phosphoribosyltransferase (HPRT) mutations in V79 cells; GEN was only marginally active and DAI inactive at this endpoint. This is the first report n the clastogenicity and mutagenicity of COUM in mammalian cells. 

And here's what some other experts say about phytoestrogens and cancer:

Postmenopausal women consuming soy isoflavones as a natural HRT may place themselves at greater risk of breast cancer. In 1996 Dr Nicholas Petrakis, University of California, San Francisco, reported that 'Prolonged consumption of soy protein isolate has a stimulatory effect on the premenopausal female breast, characterised by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells and elevated levels of estradiol.

These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein contained in soy protein isolate' (Petrakis NL et al. Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epid Bio Prev 1996; 5: 785-794).

In support of a cautionary approach to consuming soy to prevent breast cancer is Dr Bill Helferich of the University of Illinois. He has recently stated that 'there is potential for dietary genistein to stimulate the growth of estrogen-dependent tumors in humans with low circulating endogenous estrogen levels, such as those found in postmenopausal women'.  Read it for yourself!

Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Hsieh CY, Santell RC, Haslam SZ, Helferich WG.  Cancer Res 1998 Sep 1 58:17 3833-8

Abstract Genistein, found in soy products, is a phytochemical with several biological activities. In the current study,our research focused on the estrogenic and proliferation-inducing activity of genistein.

We have demonstrated that genistein enhanced the proliferation of estrogen-dependent human breast cancer (MCF-7) cells in vitro at concentrations as low as 10 nM, with a concentration of 100 nM achieving proliferative effects similar to those of 1 nM estradiol.

Expression of the estrogen-responsive gene pS2 was also induced in MCF-7 cells in response to treatment with a concentration of genistein as low as 1 microM. At higher concentrations (above 20 microM), genistein inhibits MCF-7 cell growth. In vivo, we have shown that dietary treatment with genistein (750 ppm) for 5 days enhanced mammary gland growth in 28-day-old ovariectomized athymic mice, indicating that genistein acts as an estrogen in normal mammary tissue.

To evaluate whether the estrogenic effects observed in vitro with MCF-7 cells could be reproduced in vivo, MCF-7 cells were implanted s.c. in ovariectomized athymic mice, and the growth of the estrogen-dependent tumors was measured weekly. Negative control animals received the American Institute of Nutrition (AIN)-93G diet, the positive control group received a new s.c. estradiol (2 mg) pellet plus the AIN-93G diet, and the third group received genistein at 750 ppm in the AIN-93G diet.

Tumors were larger in the genistein (750 ppm)-treated group than they were in the negative control group, demonstrating that dietary genistein was able to enhance the growth of MCF-7 cell tumors in vivo. Increased uterine weights were also observed in the genistein-treated groups.

In summary, genistein can act as an estrogen agonist in vivo and in vitro, resulting in the proliferation of cultured human breast cancer cells (MCF-7) and the induction of pS2 gene expression. Here we present new information that dietary genistein stimulates mammary gland growth and enhances the growth of MCF-7 cell tumors in ovariectomized athymic mice.

Dr Craig Dees of Oak Ridge National Laboratory has also found that soy isoflavones cause breast cancer cells to grow. He reported that 'low concentrations of genistein may stimulate MC-7 cells to enter the cell cycle'. Dees concluded that ' women should not consume particular foods (eg. soy-derived products) to prevent breast cancer'.

Dietary estrogens stimulate human breast cells to enter the cell cycle. Dees C, Foster JS, Ahamed S, Wimalasena J.  Environ Health Perspect 1997 Apr 105 Suppl 3 633-6

Abstract It has been suggested that dietary estrogens neutralize the effect of synthetic chemicals that mimic the effects of estrogen (i.e., xenoestrogens, environmental estrogens). Genistein, a dietary estrogen, inhibits the growth of breast cancer cells at high doses but additional studies have suggested that at low doses, genistein stimulates proliferation of breast cancer cells.

Therefore, if dietary estrogens are estrogenic at low doses, one would predict that they stimulate estrogen-receptor positive breast cancer cells to enter the cell cycle. Genistein and the fungal toxin zearalenone were found to increase the activity of cyclin dependent kinase 2 (Cdk2) and cyclin D1 synthesis and stimulate the hyperphosphorylation of the retinoblastoma susceptibility gene product pRb105 in MCF-7 cells.

The steroidal antiestrogen ICI 182,780 suppressed dietary estrogen-mediated activation of Cdk2. Dietary estrogens not only failed to suppress DDT-induced Cdk2 activity, but were found to slightly increase enzyme activity. Both zearalenone and genistein were found to stimulate the expression of a luciferase reporter gene under the control of an estrogen response element in MVLN cells.

Our findings are consistent with a conclusion that dietary estrogens at low concentrations do not act as antiestrogens, but act like DDT and estradiol to stimulate human breast cancer cells to enter the cell cycle.

Xenoestrogens significantly enhance risk for breast cancer during growth and adolescence. Ardies CM and Dees C. Med Hypotheses 1998 Jun 50:6 457-64

Abstract Breast cancer is one of the most common forms of cancer observed in women, and endogenous estrogen is thought to play a major role in its development. Because of this, any conditions or exposures which enhance estrogenic responses would result in an increased risk for breast cancer.

The role of xenoestrogenic compounds, such as DDT, in the etiology of breast cancer is still very controversial. In the following paper we discuss recently-published observations by ourselves and others which indicate that xenoestrogens may play a significant role in the development of breast cancer.

Specifically, we hypothesize that during periods of high growth rates and during breast development the sensitivity of breast cells to estrogenic compounds is sufficiently great for xenoestrogens to significantly enhance risk for breast cancer.

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