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Coordinate regulation of estrogen receptor β degradation by Mdm2 and CREB-binding protein in response to growth signals

Oncogene volume 32, pages 117–126 (2013)Cite this article

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Abstract

The biological actions of estrogen are mediated via estrogen receptors ERα and ERβ. Yet, other cellular signaling events that also impact ER functions have an important role in breast carcinogenesis. Here, we show that activation of ErbB2/ErbB3 tyrosine kinase receptors with growth factor heregulin-β prompts ERβ degradation by the 26S proteasome, a mechanism that requires the coactivator cAMP response element-binding (CREB)-binding protein (CBP). We found that CBP promotes ERβ ubiquitination and degradation through enhancement of the PI3-K/Akt pathway by heregulin-β, an effect potentiated by a negatively charged hinge region of ERβ. Activated Akt triggered the recruitment of E3 ubiquitin ligase Mdm2 to ERβ, which was further stabilized by CBP, resulting in ERβ poly-ubiquitination. Mutation of CBP Thr-1872 or Mdm2 Ser-186/188 Akt sites resulted in a dissociation of the ERβ-CBP-Mdm2 complex and reduced ERβ turnover. We found that the decrease in ERβ induced by heregulin-β was associated with reduced target gene promoter occupancy and enhanced proliferation of breast cancer cells. However, knockdown of Mdm2 restored endogenous ERβ levels resulting in reduction of breast cancer cell growth. These studies identify a tripartite Akt-regulated phosphorylation mechanism that functions to hamper normal ERβ activity and turnover through the concerted actions of CBP and Mdm2 in response to growth factor signaling pathways in breast cancer cells.

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Acknowledgements

We thank members of the laboratory for critical reading and useful comments. MS is supported by a doctoral award from the FHSJ (Fondation de l’Hôpital Ste-Justine), NP by the FRSQ (Fonds de la Recherche en Santé du Québec) and the FHSJ, and KS by the GRUM (Groupe de Recherche sur le Médicament de l’Université de Montréal), the FHSJ and the CIHR (Canadian Institutes of Health Research). AT is a New Investigator of the CIHR. This work was supported by grants from the CIHR, the NSERC (Natural Sciences and Engineering Research Council of Canada), the Cancer Research Society Inc. and the Canadian Foundation for Innovation.

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Authors and Affiliations

  1. Department of Biochemistry, Ste-Justine Hospital Research Center, University of Montreal, Montréal, Québec, Canada

    M Sanchez, N Picard, K Sauvé & A Tremblay

  2. Department of Obstetrics & Gynecology, University of Montreal, Montréal, Québec, Canada

    A Tremblay

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Correspondence to A Tremblay.

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Sanchez, M., Picard, N., Sauvé, K. et al. Coordinate regulation of estrogen receptor β degradation by Mdm2 and CREB-binding protein in response to growth signals. Oncogene 32, 117–126 (2013). https://doi.org/10.1038/onc.2012.19

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