PES1 promotes breast cancer by differentially regulating ERα and ERβ
PES1 promotes breast cancer by differentially regulating ERα and ERβ
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DOI：
10.1172/jci62676
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发表时间：
2012-08-01
影响因子：
15.9
通讯作者：
Ye, Qinong
中科院分区：
文献类型：
--
作者：
Cheng, Long;Li, Jieping;Ye, Qinong
乳腺癌的发生与肿瘤促进性雌激素受体α（ER α）蛋白的表达增加和肿瘤抑制性ER β蛋白的表达减少有关。然而，这一过程的机制尚不清楚。在这里，我们表明PES 1（也称为Pescadillo），一种在乳腺癌中过表达的雌激素诱导蛋白，可以调节ER α和ER β之间的平衡。我们发现PES 1通过增强ER α的转录活性同时抑制ER β的转录活性来调节许多雌激素响应基因。与ER α和ER β转录活性的调节一致，PES 1通过Hsc 70相互作用蛋白（CHIP）的羧基末端介导的泛素-蛋白酶体途径增加ER α蛋白的稳定性并降低ER β的稳定性。此外，PES 1转化正常的人乳腺上皮细胞，是雌激素诱导的裸鼠乳腺肿瘤生长所必需的。对临床样本的进一步分析表明，PES 1的表达与ER α表达呈正相关，与ER β表达呈负相关，并预测乳腺癌的良好临床结局。我们的数据表明，PES 1通过调节ER α和ER β之间的平衡促进乳腺肿瘤生长，并且可能是开发选择性调节ER α和ER β活性的药物的更好靶点。
The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor alpha (ER alpha) protein and decreased expression of tumor-suppressive ER beta protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen-inducible protein that is overexpressed in breast cancer, can regulate the balance between ER alpha and ER beta. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ER alpha while inhibiting transcriptional activity of ER beta. Consistent with this regulation of ER alpha and ER beta transcriptional activity, PES1 increased the stability of the ER alpha protein and decreased that of ER beta through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ER alpha expression and negatively with ER beta expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ER alpha and ER beta and may be a better target for the development of drugs that selectively regulate ER alpha and ER beta activities.