Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells

Abstract

Although tamoxifen (TAM) is used for the front‐line treatment and prevention of estrogen receptor‐positive (ER+) breast tumors, nearly 40% of estrogen‐dependent breast tumors do not respond to TAM treatment. Moreover, the positive response is usually of short duration, and most tumors eventually develop TAM‐resistance. Overexpression of HER2 gene is associated with TAM‐resistance of breast tumor, and suppression of HER2 expression enhances the TAM activity. Soy isoflavone genistein has been shown to have anti‐cancer activities and suppress expression of HER2 and ERα. The objective of this study was to test the hypothesis that genistein may sensitize the response of ER+ and HER2‐overexpressing breast cancer cells to TAM treatment. The combination treatment of TAM and genistein inhibited the growth of ER+/HER2‐overexpressing BT‐474 human breast cancer cells in a synergistic manner in vitro. Determination of cellular markers indicated that this synergistic inhibitory effect might be contributed in part from combined effects on cell‐cycle arrest at G 1 phase and on induction of apoptosis. Further determination of the molecular markers showed that TAM and genistein combination synergistically induced BT‐474 cell apoptosis in part by synergistic downregulation of the expression of survivin, one of the apoptotic effectors, and downregulation of EGFR, HER2, and ERα expression. Our research may provide a novel approach for the prevention and/or treatment of TAM insensitive/resistant human breast cancer, and warrants further in vivo studies to verify the efficacy of genistein and TAM combination on the growth of ER+/HER2‐overexpressing breast tumors and to elucidate the in vivo mechanisms of synergistic actions. © 2007 Wiley‐Liss, Inc.