PES1 promotes breast cancer by differentially regulating ERα and ERβ
Long Cheng, … , Xiaojie Xu, Qinong Ye
Long Cheng, … , Xiaojie Xu, Qinong Ye
Published July 23, 2012
Citation Information: J Clin Invest. 2012;122(8):2857-2870. https://doi.org/10.1172/JCI62676.
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PES1 promotes breast cancer by differentially regulating ERα and ERβ

Abstract

The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor α (ERα) protein and decreased expression of tumor-suppressive ERβ 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 ERα and ERβ. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ERα while inhibiting transcriptional activity of ERβ. Consistent with this regulation of ERα and ERβ transcriptional activity, PES1 increased the stability of the ERα protein and decreased that of ERβ 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 ERα expression and negatively with ERβ expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERα and ERβ and may be a better target for the development of drugs that selectively regulate ERα and ERβ activities.

Authors

Long Cheng, Jieping Li, Yongjian Han, Jing Lin, Chang Niu, Zhichao Zhou, Bin Yuan, Ke Huang, Jiezhi Li, Kai Jiang, Hao Zhang, Lihua Ding, Xiaojie Xu, Qinong Ye

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Figure 2

PES1 differentially modulates the dimerization and promoter occupancy of ERα and ERβ.

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PES1 differentially modulates the dimerization and promoter occupancy of...
(A and B) Coimmunoprecipitation analysis of ERα and ERβ homodimerization and ERα-ERβ heterodimerization. HEK293T cells transiently transfected with the indicated HA-, FLAG-, and MYC-tagged constructs were immunoprecipitated with (A) anti-FLAG or (B) anti-MYC antibodies, followed by immunoblotting as indicated. (C) ChIP analysis of the occupancy of PES1, ERα, or ERβ on the indicated estrogen-responsive proximal promoters (PPs) or distal enhancers (DEs) in MCF7 cells treated with 10 nM E2 for 1 hour. The β-actin promoter was included as a negative control. IgG, normal serum. Data shown are mean ± SD of triplicate measurements that have been repeated 3 times with similar results. *P < 0.05, †P < 0.01 versus respective IgG without E2. #P < 0.01 versus respective IgG with E2. (D) ChIP analysis of the occupancy of ERα or ERβ on CTSD and CCND1 promoters in MCF7 cells stably transfected with control siRNA or PES1 siRNA and treated as in C. Data shown are mean ± SD of triplicate measurements that have been repeated 3 times with similar results. *P < 0.01 versus respective control siRNA without E2. #P < 0.01 versus respective control siRNA with E2. (E) EMSA using the in vitro–translated PES1 and the biotin-labeled CdRE or mutated CdRE (mCdRE) probe. Cold probe was used for competition experiments.