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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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 7

Association of PES1 with ERα and ERβ in breast cancer.

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Association of PES1 with ERα and ERβ in breast cancer. (A and B) Express...
(A and B) Expression of ERα, ERβ, and PES1 in (A) human breast cancer tissues and (B) normal tissues adjacent to breast cancer. Representative immunohistochemical staining of PES1, ERα, and ERβ is shown at top. Original magnification, ×20. Scale bar: 100 μm. A summary of (A) 116 breast cancer tissues or (B) 92 normal breast tissues is shown below, with tissues categorized by low and high expression of PES1 and ERα or ERβ. Case 1 and case 2 refer to 2 representative samples. The P value was generated using the χ2 test. (C and D) Kaplan-Meier estimate of (C) disease-free survival and (D) overall survival in 65 patients with breast cancer who received tamoxifen treatment. Marks on graph lines represent censored samples. High PES1 and low PES1 refer to samples with high and low levels of PES1 expression, respectively. (E) Proposed model for PES1 modulation of the balance between ERα and ERβ. The estrogen-inducible protein PES1 blocks interaction of ERα with CHIP through its interaction with CHIP and instead forms a complex with ERβ and CHIP, leading to reduced degradation of ERα and increased degradation of ERβ by CHIP. In turn, PES1 enhances transcriptional activity of ERα but reduces that of ERβ through increased ERα homodimerization and decreased ERβ homodimerization and ERα-ERβ heterodimerization. Disruption of the balance between ERα and ERβ by PES1 contributes to breast tumorigenesis.