Equol is the metabolic product of daidzein, a phytoestrogenic compound found in soy. Equol possesses inherent estrogenic properties manifesting in altered hormonal response and has binding affinities for both subtypes of estrogen receptor, ERα and ERβ. In the first study of its kind, we reported that equol increases the antitumor and chemopreventive properties of tamoxifen in 7, 12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats after dietary administration (European Journal of Cancer 41: 647-654, 2005). Tamoxifen is the only pharmaceutical approved for the treatment and prevention of primary and secondary breast tumors in women at all stages of the cancer. Gross tumor data is important, but it is imperative to elucidate the molecular mechanisms underlying the antitumor and chemopreventive effects. To define the roles of the individual receptors in eliciting the increased efficacy of tamoxifen when combined with equol four cell lines with distinctive estrogen receptor expression were employed: MCF-7 (ERα+/ERβ+), S30 (ERα+/ERβ-), ERβ41 (ERα-/ERβ+), and MDA-MB-231 (ERα-/ERβ±). Viability assays reveal that the presence of both receptors is required to effectively inhibit cell growth and that the concentration of equol is a vital parameter. Equol induces proliferation at doses of 1 and 10 µM as much as estradiol while nanomolar concentrations of equol combined with 10 nM tamoxifen effectively reduce cell viability. In fact, the combination is more effective than tamoxifen alone, very similar to our in vivo results. Immunoblot data show that the effect is perhaps a result of estrogen signaling due to differences in ER expression in receptor positive cell lines following treatment. The expression patterns were both concentration and time dependent. These data suggest that ERα and ERβ ratios play a critical role in predicting the response of estrogenic compounds. Further, given that our in vitro results tightly parallel our in vivo results, we can use the present in vitro experimental model to further understand the effect of the combination of tamoxifen and equol aiming towards realizable clinical value and applications.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA