Abstract 2253: New targets of mTORC1 pathway in ER-positive cells

Abstract

Abstract mTOR complex 1 (mTORC1) regulates protein translation, autophagy, and cell growth. These cellular functions are often dysregulated in cancer, therefore identification of mTORC1 targets in control of these processes is of great interest for development of targeted cancer therapies. While rapamycin shown an effect in early clinical trials, the effectiveness of rapamycin in treatment of breast cancer has been variable. Estrogen receptor (ER) ≤ mediates the proliferative effects of estrogen and represents an important clinical target in treatment of ER-positive cancers. Tamoxifen is an anti-estrogen that has become the standard agent for the treatment of ER-positive breast cancer, where it acts as an antagonist. However, resistance to tamoxifen, and other endocrine or anti-estrogen therapies develops in many cases. One mechanism by which resistance develops is through phosphorylation of ERα, allowing it to act in estrogen-independent manner. Phosphorylation of Ser118 and Ser167 is important for transcriptional activity of ERα. The regulation of these sites is complex, involving inputs from the mTOR and MAPK signaling pathways. Importantly, ERα phosphorylation correlates with resistance to tamoxifen, and is a prognostic marker for disease progression and survival. Therefore, the goal of our study is to identify new targets of mTORC1 pathway important for growth and proliferation of ER-positive cells. Thus, inhibition of downstream components of the mTORC1 pathway together in combination with anti-estrogen therapy may prove to be an effective strategy in treatment of ER-positive cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2253. doi:1538-7445.AM2012-2253