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

The biological actions of estrogen are mediated via estrogen receptors ER alpha and ER beta. 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-beta prompts ER beta degradation by the 26S proteasome, a mechanism that requires the coactivator cAMP response element-binding (CREB)-binding protein (CBP). We found that CBP promotes ER beta ubiquitination and degradation through enhancement of the PI3-K/Akt pathway by heregulin-beta, an effect potentiated by a negatively charged hinge region of ER beta. Activated Akt triggered the recruitment of E3 ubiquitin ligase Mdm2 to ER beta, which was further stabilized by CBP, resulting in ER beta poly-ubiquitination. Mutation of CBP Thr-1872 or Mdm2 Ser-186/188 Akt sites resulted in a dissociation of the ER beta-CBP-Mdm2 complex and reduced ER beta turnover. We found that the decrease in ER beta induced by heregulin-beta was associated with reduced target gene promoter occupancy and enhanced proliferation of breast cancer cells. However, knockdown of Mdm2 restored endogenous ER beta levels resulting in reduction of breast cancer cell growth. These studies identify a tripartite Akt-regulated phosphorylation mechanism that functions to hamper normal ER beta activity and turnover through the concerted actions of CBP and Mdm2 in response to growth factor signaling pathways in breast cancer cells. Oncogene (2013) 32, 117-126; doi:10.1038/onc.2012.19; published online 20 February 2012