Role of Estrogen Receptor alpha K303R Mutation in Breast Cancer Metastasis

摘要

We reported last year that ER K303R mutation makes ER serine 305 an efficient target for both Protein Kinase A (PKA) and p21 activating kinase (PAKI), thus confers breast cancer cells expressing this mutant hypersensitivity. We report that the K303R mutant is also an efficient target for AKT activity. We have localized that Ser305 is an Akt site. In K303R ERalpha, this site is about 3 times more phosphorylated by Akt than ER Ser167, a known AkT phosphorylation site, and about 30 times more phosphorylated than Ser305 in wild type ERalpha. We utilized the mammalian two-hybrid system to test the effect of Akt-activity on the ligand-dependent activity (AF2) of wild type and K303R ER. Our data demonstrated that constitutively activated Akt2 could specially enhance the estrogen -hypersensitivity of K303R. Also, we found that AKT activity reverses MTA2 repression of WT-ER activity. Our results demonstrate that the K303R ERalpha mutation generates a novel Akt site which renders the receptor hypersensitive.