Dietary Phytoestrogens and Breast Cancer: A Complex Story Involving Dose, Target Tissue and Timing of Exposure

Genistein, found in soy products, is a phytochemical with estrogenic activity. Our research has focused on the effects dietary genistein on growth of estrogen (E)-dependent mammary tumors both in vitro and in vivo. Genistein enhances the proliferation of E-dependent human breast cancer tumor growth. Genistin, the glycoside form of genistein simulates growth similar to that of genistein and withdrawal of either genistin results in tumor regression. We have also demonstrated that soy protein isolates processed to contain low, medium and high amounts of isoflavones simulate tumor growth in a dose dependent manner. Expression of the estrogen-responsive gene, pS2 was also induced in response to treatment with dietary genistein. We also evaluated the effect of dietary genistein in the chemically-induced (NMU) mammary cancer rodent model and have demonstrated that dietary genistein stimulates growth in this model.

To evaluate whether dietary genistein interacts with current anti-estrogen breast cancer therapy such as tamoxifen (TAM) and aromatase inhibitors (AIs). We implanted E-dependent tumors into ovariectomized athymic mice and administered estradiol, estradiol plus TAM, or estradiol, TAM + dietary genistein. In these studies dietary genistein was able to negate the inhibitory effect of TAM or AIs on E-stimulated tumor growth. It is important to note that genistein has multiple biological activities and at high levels can act to inhibit cell growth. In a recent published study we have shown that the interaction of dietary genistein and TAM depend on the dose of genistein.

Genistein is present in soy as part of a complex mixture and the profile of these other bioactive compounds plays an important role; we will present data on how the profile of soy bioactive compounds can modulate genistein stimulated estrogen-dependent tumor growth. In recent years there have been several published reports from human studies that suggest that soy is safe for breast cancer (BC) survivors – these results raise an important issues between the difference in the consumption of soy foods and highly enriched/purified genistein-containing dietary supplements and BC survivors. Much of the confusion between human and pre-clinical studies can be resolved by the timing/duration of administration, the form in which genistein is consumed and the specific subpopulation of BC survivors.

In summary, from the pre-clinical studies, genistein can act as an estrogen agonist resulting in proliferation of E-dependent human breast cancer cells in vivo and can negate the inhibitory effects of TAM and AIs on E-stimulated growth of MCF-7 cell tumors (in vivo) implanted into ovariectomized athymic mice. These results suggest that women with estrogen-dependent BC should avoid dietary supplements and soy ingredients high in genistein.