PES1 promotes breast cancer by differentially regulating ERα and ERβ
Long Cheng, … , Xiaojie Xu, Qinong Ye
Long Cheng, … , Xiaojie Xu, Qinong Ye
Published August 1, 2012; First published July 23, 2012
Citation Information: J Clin Invest. 2012;122(8):2857-2870. https://doi.org/10.1172/JCI62676.
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Category: Research Article

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 1

PES1 differentially regulates transcriptional activity of ERα and ERβ and expression of their target genes.

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PES1 differentially regulates transcriptional activity of ERα and ERβ an...
(A and B) Luciferase reporter assays of ERα and ERβ transcriptional activity in (A) MCF7 or (B) SKBR3 cells transiently transfected with ERE-LUC and PES1, SRC1, GRIP1, XRCC1, or BARD1 with or without ERα or ERβ and 24-hour treatment with 10 nM E2, 1 nM PPT, or 1 nM DPN. Results shown are mean ± SD of 3 independent experiments. ‡P < 0.01, *P < 0.01, #P < 0.01, †P < 0.01 versus empty vector in the (A) absence or (B) presence of ERα or ERβ with vehicle (–), E2, PPT, and DPN, respectively. (C) Luciferase reporter assays in MCF7 cells stably transfected with PES1 siRNA or PES1 siRNA plus siRNA-resistant PES1 (PES1-R) and treated as above. Immunoblot analysis of PES1 expression is shown. Results shown are mean ± SD of 3 independent experiments. *P < 0.01, #P < 0.01, †P < 0.01 versus control siRNA with E2, PPT, and DPN, respectively. (D) Real-time RT-PCR analysis of 47 genes identified by cDNA microarray in our study and 4 genes identified in other studies (CCND1, CTSD, E2F1, and C-FOS) in PES1 knockdown MCF7 cells treated or not treated with E2 (+E2 or –E2, respectively) for 24 hours. Data shown are mean ± SD of triplicate measurements that have been repeated 3 times with similar results. *P < 0.05, #P < 0.01 versus control siRNA without E2. ‡P < 0.05, †P < 0.01 versus control siRNA with E2. (E) Immunoblot analysis of estrogen-responsive gene expression in PES1 knockdown MCF7 cells.