c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligand-activated transcription factors. Similar to other steroid hormone receptors, estrogen receptor alpha (ER alpha) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ER alpha associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ER alpha and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ER alpha can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ER alpha phosphorylation by c-Abl stabilizes ER alpha, resulting in enhanced ER alpha transcriptional activity and increased expression of endogenous ER alpha target genes. Furthermore, ER alpha phosphorylation at the Y-219 site affects DNA binding and dimerization by ER alpha. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Abl-induced accumulation of ER alpha and enhancement of ER alpha transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ER alpha function. Moreover, the ER alpha (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ER alpha expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer. Oncogene (2010) 29, 2238-2251; doi: 10.1038/onc.2009.513; published online 25 January 2010