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.Oncogene advance online publication, 20 February 2012; doi:10.1038/onc.2012.19.