ABSTRACT
Resistance to anti-estrogen therapy is a major clinical concern in treatment of breast cancer. Estrogen-independent phosphorylation of estrogen receptor alpha, specifically on Ser167, is one of the contributing causes to development of resistance, and a prognostic marker for the disease. Here, we dissect the signaling pathways responsible for Ser167 phosphorylation. We report that the mTOR/S6K1 and MAPK/RSK contribute non-overlapping inputs into ERalpha activation via Ser167 phosphorylation. This cooperation may be targeted in breast cancer treatment by a combination of mTOR and MAPK inhibitors.
Subject(s)
Estrogen Receptor alpha/metabolism , Mitogen-Activated Protein Kinase Kinases/metabolism , Protein Kinases/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Humans , Phosphorylation , Serine/metabolism , Signal Transduction , TOR Serine-Threonine Kinases , Transcription, GeneticABSTRACT
The 40 S ribosomal S6 kinase 1 (S6K1) acts downstream of mTOR (mammalian target of rapamycin) and is sensitive to inhibition by rapamycin. The chromosomal region 17q23 containing the RPS6KB1 gene is frequently amplified in breast cancer cells, leading to S6K1 overexpression. The role of S6K1 in disease development and progression is supported by the observation that S6K1 overexpression is associated with poor prognosis in breast cancer patients. However, the identity of mammary cell-specific S6K1 targets is not well understood. In this study, we report that overexpression of S6K1 endows breast cancer cells with a proliferative advantage in low serum conditions and enhanced sensitivity to rapamycin. We investigate the molecular mechanism behind this observation to show that S6K1 regulates estrogen receptor alpha (ERalpha) by phosphorylating it on serine 167, leading to transcriptional activation of ERalpha. By contributing to the activation of ERalpha, S6K1 promotes ERalpha-mediated cell proliferation and may be a target of therapeutic intervention in breast cancer.
