Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells
Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells
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DOI：
10.1002/mc.20300
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发表时间：
2007-07-01
影响因子：
4.6
通讯作者：
Zhou, Jin-Rong
中科院分区：
文献类型：
--
作者：
Mai, Zhiming;Blackburn, George L.;Zhou, Jin-Rong
尽管他莫昔芬（TAM）用于一线治疗和预防雌激素受体阳性（ER+）乳腺肿瘤，但近40%的雌激素依赖性乳腺肿瘤对TAM治疗无反应。此外，阳性反应通常持续时间较短，大多数肿瘤最终会产生TAM抗性。HER 2基因过表达与乳腺癌TAM耐药相关，抑制HER 2表达可增强TAM活性。大豆黄酮染料木黄酮已被证明具有抗癌活性，并抑制HER 2和ER α的表达。本研究的目的是检验染料木黄酮可能使ER+和HER 2-过表达乳腺癌细胞对TAM治疗的反应敏感的假设。TAM和染料木黄酮的联合处理在体外以协同方式抑制ER+/HER 2-过表达的BT-474人乳腺癌细胞的生长。细胞标志物的测定表明，这种协同抑制作用可能部分来自于对细胞周期阻滞在G期和诱导细胞凋亡的联合作用。分子标记物的进一步测定显示，TAM和染料木黄酮组合协同诱导BT-474细胞凋亡，部分通过协同下调凋亡效应物之一生存素的表达，以及下调EGFR、HER 2和ER α的表达。我们的研究可能为预防和/或治疗TAM不敏感/耐药的人乳腺癌提供一种新的方法，并保证进一步的体内研究，以验证染料木素和TAM组合对ER+/HER 2-过表达乳腺肿瘤生长的有效性，并阐明体内协同作用的机制。(C)2007 Wiley-Liss，Inc.
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 sciflavone genistein has been shown to have anti-cancer activities and suppress expression of HER2 and ER alpha. 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, 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 ER alpha 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. (C) 2007 Wiley-Liss, Inc.