染料木黄酮通过ER-erbB-2相互关联和 p27/kip1下调来诱导增强 ER-阳性/erbB-2-超量表达乳腺癌的生长加速_杨晓荷

针对病种：乳腺癌

发表时间：2010年4月

发表国家：英国

登载刊物：致癌作用

研究单位：美国俄克拉荷马大学健康科学中心病理学系等

研究人员：杨晓荷，安 D 托尔等

主要结论：在 ER 阴性 (ER−) / erbB-2 超量表达的 (erbB-2 +) 细胞中，染料木黄酮已被证明可以通过其酪氨酸激酶抑制活性对细胞进行生长抑制，我们的数据表明 ER 和 erbB-2 的相伴共表达使乳腺癌在相当大的剂量范围内特别容易受到金雀异黄素的生长促进作用.

Carcinogenesis, 2010, 31(4):695-702.

Genistein induces enhanced growth promotion in ER-positive/erbB-2-overexpressing breast cancers by ER-erbB-2 cross talk and p27/kip1 downregulation

Xiaohe Yang, Ann D.Thor, et al

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; et al

Genistein is a major isoflavone with known hormonal and tyrosine kinase-modulating activities. Genistein has been shown to promote the growth of estrogen receptor positive (ER+) MCF-7 cells. In ER-negative (ER−)/erbB-2-overexpressing (erbB-2+) cells, genistein has been shown to inhibit cell growth through its tyrosine kinase inhibitor activity. The effects of genistein on cell growth and tamoxifen response in ER+/erbB-2-altered breast cancers (known as luminal type B and noted in ∼10 to 20% of breast cancers) have not been well explored. Using erbB-2-transfected ER+ MCF-7 cells, we found that genistein induced enhanced cellular proliferation and tamoxifen resistance when compared with control MCF-7 cells. These responses were accompanied by increased phosphorylation of ERα and ER signaling, without increase in ER protein levels. Genistein-treated MCF-7/erbB-2 cells also showed enhanced activation/phosphorylation of erbB-2, Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase. Blockade of the phosphatidylinositol 3-kinase and/or MAPK pathways abrogated genistein-induced growth promotion, suggesting that genistein effects involve both critical signaling pathways. We also found that p27/kip1 was markedly downregulated in genistein-treated MCF-7/erbB-2 cells. Overexpression of p27/kip1 attenuated genistein-mediated growth promotion. In aggregate, our data suggest that the concomitant coexpression of ER and erbB-2 makes breast cancers particularly susceptible to the growth-promoting effects of genistein across a wide range of doses. The underlying mechanisms involve enhanced ER–erbB-2 cross talk and p27/kip1 downregulation.

英国《致癌作用》，2010年4月

染料木黄酮通过ER-erbB-2相互关联和 p27/kip1下调来诱导增强 ER-阳性/erbB-2-超量表达乳腺癌的生长加速

杨晓荷，安 D 托尔等

美国俄克拉荷马大学健康科学中心病理学系等

金雀异黄素是知名的主要异黄酮激素，拥有调节酪氨酸激酶的活性。染料木黄酮已被证明可以促进MCF-7 细胞中雌激素受体阳性（ER +）的生长。在 ER 阴性 (ER−) / erbB-2 超量表达的 (erbB-2 +) 细胞中，染料木黄酮已被证明可以通过其酪氨酸激酶抑制活性对细胞进行生长抑制。金雀异黄素对细胞生长的作用和三苯氧胺在 ER + /erbB-2 改变的乳腺癌（称为 B 型管腔，并指出在 ∼10 至 20%的乳腺癌）中的反应没有被充分探讨。我们使用 erbB-2 转录 ER + MCF-7 细胞，与对照 MCF-7 细胞相比，发现金雀异黄素诱导细胞增殖的增强和三苯氧胺的抗性。这些反应伴随着 e α增强的磷酸化和 ER 的信号，但不会增加 ER的蛋白水平。金雀异黄素处理的 MCF-7/erbB-2 细胞也表现出增强erbB-2的活化/磷酸化、 Akt 和有丝分裂活化的蛋白激酶 (MAPK) / 细胞外信号调节激酶。磷脂酰肌醇 3-激酶的阻断和（或） MAPK 通路取消了染料木黄酮诱导的生长促进，暗示金雀异黄素的作用涉及这两个关键的信号通路。我们还发现，p27/kip1在金雀异黄素处理的 MCF-7/erbB-2 细胞中明显下调。P27/kip1 的过度表达减弱了染料木素介导的生长加速。总的来说，我们的数据表明 ER 和 erbB-2 的相伴共表达使乳腺癌在相当大的剂量范围内特别容易受到金雀异黄素的生长促进作用。这种基本机制包含增强的 ER- erbB-2 交叉联系和 p27/kip1的下调。