A phosphotyrosine switch determines the antitumor activity of ERβ
A phosphotyrosine switch determines the antitumor activity of ERβ
复制标题
磷酸酪氨酸开关决定 ER beta 的抗肿瘤活性
DOI：
10.1172/jci74085
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发表时间：
2014-08-01
影响因子：
15.9
通讯作者：
Li, Rong
中科院分区：
文献类型：
--
作者：
Yuan, Bin;Cheng, Long;Li, Rong
雌激素受体ER α和ER β具有相当大的序列同源性，但对乳腺癌细胞增殖产生相反的作用。虽然ER α在乳腺肿瘤中的增殖作用已得到很好的表征，但ER β的抗肿瘤活性是否能在乳腺癌细胞中动员尚不清楚。在这里，我们已经表明，存在于ER β中而不是ER α中的酪氨酸残基（Y36）的磷酸化决定了ER β特异性转录激活，并且是培养物和小鼠异种移植物中ER β依赖性抑制癌细胞生长所必需的。此外，c-ABL酪氨酸激酶和EYA 2磷酸酶直接和直接控制Y36的磷酸化状态和随后的ER β功能。一个非磷酸化的，转录活性的ER β突变体保留抗肿瘤活性，但绕过上游调控。Y36的磷酸化是ER β介导的辅激活因子向ER β靶启动子募集所必需的。在人类乳腺癌样本中，ER β中Y36磷酸化水平升高与高水平的c-ABL但低水平的EYA 2相关。此外，与总ER β相比，磷酸化Y36特异性ER β的存在与II期和III期疾病患者的无病生存率和总生存率密切相关。总之，这些数据确定了调节ER β特异性抗肿瘤活性的信号通路，并具有作为癌症治疗的预后工具和分子靶点的潜力。
Estrogen receptors ER alpha and ER beta-share considerable sequence homology yet exert opposite effects on breast cancer cell proliferation. While the proliferative role of ER alpha in breast tumors is well characterized, it is not clear whether the antitumor activity of ER beta can be mobilized in breast cancer cells. Here, we have shown that phosphorylation of a tyrosine residue (Y36) present in ER beta, but not in ER alpha, dictates ER beta-specific activation of transcription and is required for ER beta-dependent inhibition of cancer cell growth in culture and in murine xenografts. Additionally, the c-ABL tyrosine kinase and EYA2 phosphatase directly and diametrically controlled the phosphorylation status of Y36 and subsequent ER beta function. A nonphosphorylatable, transcriptionally active ER beta mutant retained antitumor activity but circumvented control by upstream regulators. Phosphorylation of Y36 was required for ER beta-mediated coactivator recruitment to ER beta target promoters. In human breast cancer samples, elevated phosphorylation of Y36 in ER beta correlated with high levels of c-ABL but low EYA2 levels. Furthermore, compared with total ER beta, the presence of phosphorylated Y36-specific ER beta was strongly associated with both disease-free and overall survival in patients with stage II and III disease. Together, these data identify a signaling circuitry that regulates ER beta-specific antitumor activity and has potential as both a prognostic tool and a molecular target for cancer therapy.