Conventional medicine generally ignores ordinary foods as therapeutic interventions against cancer. Compared with pharmaceuticals, common foods as medicines are vastly under-researched. But National Cancer Institute studies have shown that there are powerful cancer protectants and tumor shrinking factors contained in many humble food products. Fermented whole soy foods are probably the best example.

The impact of soybean foods upon breast cancer is a complex and intriguing subject. Fermented, whole soy products such as miso, natto, tempeh and a novel medical food product called Haelan 951, contain a host of agents that are particularly beneficial in preventing, and treating tumors of the breast, particularly those classified as estrogen receptor positive (ER+) (Birt, D, et al. Pharmacology & Therapeutics. 2001; 90 (2–3): 157–177).

About 77% of all breast cancers are ER+. Growth of these tumors is enhanced by estrogen, which, under many circumstances becomes a natural, endogenous carcinogen. A small portion of breast cancers—about 23%—are estrogen receptor negative (ER–), because these tissue cells seem to be impervious to estrogen, regardless of the hormone’s concentration in the blood. But even tumors of this type may respond to soy-based therapy.

Medical opinions about the effects of soy in breast cancer have heretofore been rather contradictory, and many clinicians have taken a frankly negative stance on consumption of soy by women at risk. But a substantial body of data suggest the opposite position is more reasonable: fermented soy foods used as an anti-cancer monotherapy or especially in combination with tamoxifen, often shrink breast tumors.

Epidemiological data are quite consistent in indicating that fermented soy foods confer a certain degree of protection against tumors, especially when consumption begins in childhood (Colditz GA, Frazier AL. Cancer Epidem Biomarker Prevent 1995; 4: 567–71). In general, populations with diets rich in fermented soy products enjoy a much lower incidence of breast cancer, particularly among premenopausal women (Messina MJ, Loprinzi CL. J Nutrition. 2001; 131: 3095S–3108S).

The secret of this protective action is in the ability of metabolized soy to mimic the principal culprit associated with breast cancer: estrogen.

“Musical Chairs” at Estrogen Receptor Sites

Cell surface receptors can be thought of as tiny portals into the cells. Receptors bind very specific biochemicals circulating in the blood. There are as many types of receptors as there are tissue types, each with its own internal architecture that perfectly accommodates the molecular structure of a specific hormone or signaling molecule.

Biochemicals bind to cellular receptors with selective affinities, depending on how closely their molecular shapes fit one another. Often a compound slips crudely into a receptor’s binding site, and fits well enough to block out other compounds. This amounts to a chemical competition to fill receptor sites.

Metastatic breast cancer begins when circulating estrogen binds with receptors on the surfaces of cells of an in-situ pre-malignant breast lesion. Women with high estrogen levels suffer higher incidence of breast cancer than those with lower levels. There are also data showing tumors of the breast grow more slowly in patients with lower estrogen levels (Peterson G, Barnes S. Cell Growth Differ 1996; 7: 1345–51).

Soybean plants are rich in estrogen-like compounds called phytoestrogens, in particular, a class of agents called isoflavones, that provide anti-cancer protection by harmlessly binding to estrogen receptors in breast tissue, effectively blocking out estrogen itself. This effect tends to shield breast tissue from the carcinogenic effects of the actual hormone.

Soy isoflavones bind to breast tissue estrogen receptors, but much more weakly than human estrogens or synthetic estrogen analogues. Isoflavone, which is metabolized by the body as genistein or daidzein, acts as an anti-estrogen: strong enough to bind with estrogen receptors in the breast, but too inert to initiate the cascade of events that ends in metastatic tumors, the way estrogen does.

Genistein and daidzein both resemble the structure of 17-β-estradiol. Both of these metabolites bind to a critical estrogen receptor. The result of this coupling has a virtually neutral effect on breast tissue, but it deprives actual estrogen of receptor sites.

Soy phytoestrogens are 100,000 times weaker in their estrogenic effect, just as their binding affinity to the estrogen receptor is much weaker than estrogen’s. Consumption of fermented soy products overcomes weak binding by sheer volume. Women who eat significant amounts of soy have levels of isoflavones that are 10,000 times higher than women who don’t eat soy. The isoflavones compete vigorously for receptor binding sites, explaining in part, the anti-cancer effects of specific soy-products.

In essence, isoflavones play a game of musical chairs with the body’s endogenous estrogen with respect to the estrogen receptor sites. When the music stops, isoflavone metabolites fill many of the breast cell receptors, leaving estrogen still drifting, unbound, in the bloodstream.

But that’s not the whole story. Isoflavones from soybeans act as anti-cancer agents and tumor shrinking factors by way of numerous other mechanisms.

Neutralizing Estrogen

Soy isoflavones have a number of physiologic effects that all contribute to a neutralization of adverse effects associated with estrogen. At high concentrations, genistein has strong anti-proliferative effects on both ER+ and ER– cancer cells. This may have to do with down-regulation of signal transduction.

There are a number of studies indicating soy isoflavones also induce synthesis of Sex Hormone Binding Globulin (SHGB), a protein that binds to estrogen creating a much larger, bulky molecule that is no longer capable of binding with estrogen receptors (Pino AM, et al. J. Clin Endocrinol Metab 2000, 85(8), p2797–800. Kurzer MS. J. Nutr 2002, 132(3-suppl), p570s–73s. Watanabe S, Uesugi S, Kikuchi Y. Biomed & Pharmacotherapy, 2002, 56(6), p302–312). This conclusion is not unanimous, however. Martini et al. in their 1999 study in the journal, Nutrition and Cancer state they found no effect on SHBG. Dose and product consumed were at issue.

There is evidence that isoflavones can inhibit the synthesis of estrogen itself. One study, by Dr. Jane Lu of the University of Texas Medical School at Galveston, found that healthy women who eat soy have circulating estrogen levels 30–40% lower than women who don’t (Lu IJ, et al. Cancer Epidemiol Prev. 1996, 5 p63–70. Lu IJ, et al. J Clin Endocrinol Metab, 2001, 86, p3045–52).

The isoflavones seem to alter the estrogen receptor itself, so estrogen binding is less competent. They thus tone down estrogen-binding, and diminish the virulence of the estrogen binding effects when binding does occur.

Just as with cholesterol, there are “good” and “bad” types of estrogen. Isoflavones from fermented soy seem to influence the way estrogen itself is metabolized, favoring production of the “good” 2-OHE metabolites, over the inflammatory 16-OHE forms. The higher the ratio of 2-OHE to 16-OHE, the better from the viewpoint of breast health.

Fermentation is Critical

Fermentation of whole soy creates far more effective therapeutic and cancer protective compounds than those found in raw soy beans. This is because in the fermentation process, yeast and bacteria reduce isoflavones into compounds of smaller molecular weights. Between two and twelve times smaller than isoflavones in raw soy, these fermented isoflavones, including genistein, diadzein, and equol, are more “bio-available,” and they reach their designated targets—estrogen receptors—far more effectively.

For cancer patients there’s the additional fact that whole, fermented soy metabolites stimulate an immune response that’s critical in raising survival rates. The entire gamut of immune responses is ramped up by soy derived compounds. The cellular immune response is particularly sensitive. CD3, CD4 and CD8 cells, as well as natural killer (NK) cells all show increased proliferation and activity in response to soy metabolites (Zhang Y, et al. J Nutr 1999, 129, p399–405). Macrophages also increase their activity by as much as 700% among cancer patients regularly consuming a nutraceutical fermented soy beverage originally developed in China and sold in the US as Haelan 951 (Watanabe S, Uesugi S, Kikuchi Y. Biomed & Pharmacotherapy, 2002, 56(6), p302–312).

The distinction between Haelan 951 and ordinary soy beverages (i.e. “soy milk”) is the fermentation and nitrogenation processes involved in its production. These processes that increase bioavailibity and absorption of key plant compounds naturally occurring in soy, such as isoflavones, protease inhibitors, saponins, phytoesterols, and phytic acid. This adjuvant micronutrient-rich beverage increases immune competence, improves hormonal balance, and reduces inflammation and oxidative stress that impacts chronic and acute illness.

Furthermore, whole soy itself slows down the rate of human cancer cell division, a key goal in any therapeutic intervention. The compound thought to be responsible for this effect is called IP-6 (Watanabe S, Aldercreutz H. ACS Symp Ser. 1998, 702, p198–208. Middleton Jr E., Adv Exp Med Biol. 1998, 439, p175–182. Zava DT, Duwe G. Nutr Cancer. 1997, 27(1), p31–40. Birst DF, et al. Pharm & Therapeutics. 2001, 90(2,3), p157–77). In rodent studies, the impact of IP-6 is intriguing. After five weeks of treatment with IP-6, 80% of animals with mammary tissue tumors were cancer free. In those with residual tumors, IP-6 resulted in tumor shrinkage to less than 2%. In the untreated control group, none of the tumors disappeared (Coldham NG, Sauer MJ. Tox Appl Pharm. 2000, 164(2), p206–15).

Direct Therapeutic Effects

What about women who have breast tumors? Do soy products provide any therapeutic benefits for them?

Several studies show that breast tumors shrink when cancer patients are placed on a soy-rich diet. For all the impact that isoflavones have as cancer protectants, soy varieties bred with no isoflavones show greater tumor shrinkage than therapeutic products made from pure isolates of isoflavones. It turns out that the most potent agent of all in abetting tumor shrinkage is a downstream fermentation metabolite of daidzein called equol.

The equol metabolite heads right for estrogen receptors for which it has a very strong affinity. Equol is, essentially, a very targeted active agent. Because equol has such a strong affinity estrogen receptors, it actually infiltrates into breast cells themselves, and can be found in biopsies collecting in breast tissue cells.

The unfortunate catch is that only 30% of the general population is able to convert daidzein from soy into equol. Some of this variation is accounted for by differences in intestinal flora. However, some researchers have conjectured that equol itself might be modified by the fermentation process itself. This might improve the ability of some individuals to produce higher levels of equol.

Cutting Through the Controversy

Epidemiology and demographics should be sufficient to generate intense research on the potential for soy-based diets to confer immunity to breast cancer, and to add soy to the list of true therapeutic options. While there is clearly room for more well-designed studies on the immunology and biochemistry of whole fermented soy foods, the existing data show that there are clear biochemical mechanisms suggestive of anti-tumor effects.

Unfortunately, the big picture perspective is clouded with confusion. Breast cancer patients face a quandary when health care professionals continually flip-flop on whether to recommend soy products, especially as a therapeutic intervention for breast cancer.

Some of the confusion arises because physicians fail to distinguish phytoestrogens and their beneficial isoflavone metabolites—especially equol—from human hormone estrogen and its estradiol metabolites. Many clinicians assume all estrogens are generically equivalent and they indiscriminately discourage soy consumption for women at risk.

Some oncologists contend that soy estrogens can bind to the anti-cancer compound tamoxifen, thus neutralizing its potency. But recent research suggests quite the contrary conclusion. There appears to be a synergy, as yet unexplained, between soy products and tamoxifen. These studies indicate that in terms of estrogen receptor binding, the combination of soy and tamoxifen works better than either one separately.

A University of Illinois study found that tamoxifen monotherapy reduced breast tumors by 29% while Haelan 951 used alone reduced the tumors by 37%. However, the combination of tamoxifen and soy resulted in an impressive 62% tumor reduction rate.

It may be that the receptor blocking, immune stimulating and tumor shrinking effects of fermented soy metabolites are more effective than the heavy hammer of chemotherapy.

Much needs to be studied regarding a holistic dietary approach to breast cancer treatment and prevention. But the epidemiological evidence and a growing set of experimental results beg for rigorous large-scale clinical studies sooner rather than later.