Abstract P2-05-06: Effects of a soy isoflavone in breast cancer treatment

Background : Isoflavones are phytoestrogens that may be effective in preventing osteoporosis, reducing cardiovascular events, and improving menopausal symptoms such as hot flash due to their estrogen-like actions. Isoflavones are currently used as a supplement for improving symptoms of menopause. Epidemiological studies have shown that ingestion of soy products may also reduce the risk of breast cancer, and antitumor effects on hormone receptor (HR)-positive breast cancer cells have been shown in vitro for equol, an isoflavone metabolite. Equol binds to estrogen receptors (ERα, β) and is thought to antagonize ERα-estradiol binding in the presence of estradiol. Since equol shows an antiestrogenic effect, similar to that of the hormonal agent tamoxifen, it is thought that equol acts as a selective estrogen receptor modulator (SERM), but the mechanism is still unclear. In this study, we evaluated the antitumor effects of equol alone and in combination with existing therapeutic agents in HR-positive breast cancer cells, and examined the mechanism of these effects. Methods : The antitumor effects of equol alone and in combination with hormone drugs (4-hydroxytamoxifen (Tam), fulvestrant (Ful)) and chemotherapeutic agents (paclitaxel (Ptx), doxorubicin (Dox)) were examined using a MTS assay. Combination indexes (CIs) were determined in HR-positive MCF-7, T-47D, and ZR-75-1 cell lines. The mechanisms of the drug effects were evaluated by Western blot for assessment of changes in chemoresistance factors at the protein level. Results : In MCF-7, T-47D and ZR-75-1 cells, there was a concentration-dependent antitumor effect of equol and of the other hormonal agents. CIs showed an antagonistic effect of equol with Tam and a synergistic effect with Ful in all cell lines. Equol also had an antagonistic effect with the two chemotherapeutic agents, with the strongest antagonism occurring at a low dose of equol. Western blot showed that ER, PgR, Cyclin D1 and Bcl-2 were upregulated via ER at a low concentration of equol, similarly to the effect of 17-β-estradiol (E2), and ER, PgR, Cyclin D1 and Bcl-2 were downregulated at a high concentration, similarly to the effect of Tam. In addition, ER, PgR and cyclin D1 were downregulated with the combination of equol and Tam, while the expression of Bcl-2, a chemoresistance factor, increased. Conclusion : These results suggest that equol has a concentration-dependent antitumor effect in HR-positive breast cancer cell lines and may antagonize the effect of existing therapeutic agents (hormone drugs and chemotherapeutic agents). In particular, it was considered that in combination of equol and Tam, the apoptosis inducing action of each drug was attenuated and antagonistic effect was shown. Citation Format: Hatono M, Ikeda H, Taira N, Suzuki Y, Kajiwara Y, Kawata K, Takahashi Y, Tsukioki T, Kochi M, Iwamoto T, Shien T, Doihara H. Effects of a soy isoflavone in breast cancer treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-06.