Resistance to tamoxifen-induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer
Resistance to tamoxifen-induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer
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DOI：
10.1002/ijc.1614
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发表时间：
2002-01-20
影响因子：
6.4
通讯作者：
Yen, SH
中科院分区：
文献类型：
--
作者：
Chung, YL;Sheu, ML;Yen, SH
Her 2/neu的过表达涉及对抗雌激素他莫昔芬（TAM）的抗性的发展，所述TAM通过与雌激素受体（ER）的相互作用发挥其抑制作用。尽管Her 2/neu和ER被认为是人类乳腺癌细胞中重要的细胞存活/死亡因子，但它们是否以及如何相互作用以赋予对激素治疗的抗性尚不清楚。这促使我们研究TAM作用的调节是否通过Her 2/neu通路发生，以及靶向Her 2/neu通路和ER通路之间的相互作用是否有益。有两种形式的ER定位于细胞膜和细胞核。我们首次发现Her 2/neu在细胞膜上直接与ER相互作用。然后，我们研究了Her 2/neu过表达在TAM耐药乳腺癌细胞中调节细胞膜ER途径的作用，以及这种相互作用在凋亡信号传导中的性质。TAM耐药的缓解与Her 2/neu下调和ER上调相关。TAM诱导的细胞凋亡发生后立即从细胞膜ER的Her 2/neu的解离。这些结果证明了一种新的机制，Her 2/neu调节细胞膜ER偶联的凋亡和可能参与乳腺癌细胞的TAM耐药。TAM的抗增殖作用依赖于细胞膜ER信号转导和细胞核ER基因调控的整合。细胞膜ER/Her 2/neu通路和细胞核ER/RAR通路的协同调节可能为ER阳性、Her 2/neu过表达的乳腺癌的治疗提供新的途径。(C)2002 Wiley-Liss，Inc.
Overexpression of Her2/neu is implicated in the development of resistance to the antiestrogen tamoxifen (TAM) that exerts its inhibitory effect through interaction with estrogen receptor (ER). Whereas Her2/neu and ER are believed to be important cell survival/death factors in human breast cancer cells, if and how they interact to confer resistance to hormone therapy is not known. This prompted us to investigate whether modulation of the effect of TAM occurs via the Her2/neu pathway and whether targeting the interaction between the Her2/neu pathway and the ER pathway is beneficial. There are 2 forms of ER that are localized to the cell membrane and to the nucleus. For the first time, we found that Her2/neu directly interacts with ER at the cell membrane. We then investigated the role of Her2/neu overexpression in the regulation of the cell membrane ER pathway in TAM-resistant breast cancer cells and the nature of this interaction in apoptotic signaling. Relief of TAM resistance was associated with Her2/neu downregulation and ER upregulation. TAM-induced apoptosis occurred immediately after dissociation of Her2/neu from cell membrane ER. These results demonstrate a novel mechanism by which Her2/neu regulates the cell membrane ER-coupled apoptosis and the possible involvement of the Her2/neu in TAM resistance of breast cancer cells. Moreover, the antiproliferative activity of TAM should rely on the integration between the signal transduction from the cell membrane ER and the gene regulation by the nuclear ER. Coordinated modulation on the cell membrane ER/Her2/neu pathway and the nuclear ER/RAR pathway may provide a new approach for treatment of ER-positive, Her2/neu overexpressing breast cancer. (C) 2002 Wiley-Liss, Inc.