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
ERalpha. 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
ERalpha 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.