PES1 promotes breast cancer by differentially regulating ERα and ERβ

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, People’s Republic of China.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2012; 122(8):2857-70. DOI: 10.1172/JCI62676
Source: PubMed


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.

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    • "While in MCF7 cells, the degradation of ERα does not change significantly, but TSC enhances degradation of ERα in T47D cells (Fig. 3). Interestingly, TSC also decreased the expression of ERβ in MCF7 (Fig. 3F); however, ERβ was not expressed in T47D [16]. These differences may be due to the heterogeneity of cancer cell lines, though clearly more follow-up studies are needed to verify this supposition. "
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    ABSTRACT: The Tongshu Capsule (TSC) is a prevalent form of traditional Chinese medicine widely used for its purported effects in treating mammary gland hyperplasia and inflammation. Though successful in several clinical studies, there is no clear evidence as to why TSC has a positive treatment effect, and little known about underlying mechanism that may account for it. In this study, we examined the effects of TSC and found that it has a comparatively strong growth inhibition on ERα positive breast cancer cells. TSC seems to cause G1 cell cycle arrest instead of apoptosis. Interestingly, TSC also down-regulated the expression of ERα and Cyclin D1. Consistently, TSC suppressed E2 mediated ERα downstream gene expression and cell proliferation in ERα positive breast cancer cell lines MCF7 and T47D. Depletion of ERα partially abolished the effects of TSC on the decrease of Cyclin D1 and cell viability. Our findings suggest that TSC may have therapeutic effects on ERα positive breast cancers and moreover that TSC may suppress breast epithelial cell proliferation by inhibiting the estrogen pathway.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "The development of estrogen responsive tumors could be modulated by ER through controlling transcription of various genes thereby influencing tumor phenotype [22], [23]. Approximately 70% of all human breast cancers are ERα-positive and dependent on hormones for proliferation. "
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    ABSTRACT: Bisphenol AF (BPAF)-induced transcriptional activity has been evaluated by luciferase reporter assay. However, the molecular mechanism of BPAF-induced endogenous transcription in human breast cancer cells has not been fully elucidated. In the present study, we investigated the effect and mechanism of BPAF-induced endogenous transcription detected by real-time PCR in human breast cancer cells. We found that BPAF stimulated transcription of estrogen responsive genes, such as trefoil factor 1 (TFF1), growth regulation by estrogen in breast cancer 1 (GREB1) and cathepsin D (CTSD), through dose-dependent and time-dependent manners in T47D and MCF7 cells. Gene-silencing of ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER) by small interfering RNA revealed that BPAF-induced endogenous transcription was dependent on ERα and GPER, implying both genomic and nongenomic pathways might be involved in the endogenous transcription induced by BPAF. ERα-mediated gene transcription was further confirmed by inhibition of ER activity using ICI 182780 in ERα-positive T47D and MCF7 cells as well as overexpression of ERα in ERα-negative MDA-MB-231 breast cancer cells. Moreover, we utilized Src tyrosine kinase inhibitor PP2 and two MEK inhibitors PD98059 and U0126 to elucidate the rapid nongenomic activation of Src/MEK/ERK1/2 cascade on endogenous transcription. Our data showed that BPAF-induced transcription could be significantly blocked by PP2, PD98059 and U0126, suggesting activation of ERK1/2 was also required to regulate endogenous transcription. Taken together, these results indicate that BPAF-induced endogenous transcription of estrogen responsive genes is mediated through both genomic and nongenomic pathways involving the ERα and ERK1/2 activation in human breast cancer cells.
    Full-text · Article · Apr 2014 · PLoS ONE
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    ABSTRACT: Alteration of the ERα/ERβ balance is a critical step in breast cancer development and progression, and selective restoration of the activity of estrogen receptors has been proposed as one of the major therapeutic approaches for breast cancer. In this issue of JCI, Cheng et al. show that, by differentially modulating the stability of ERα and ERβ, PES1 increases the ERα/ERβ ratio and triggers breast tumor growth. These findings highlight PES1 as a potential target for the treatment of breast cancer.
    Preview · Article · Jul 2012 · The Journal of clinical investigation
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