Identification and characterization of S6K1 targets in mammary cell proliferation

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DESCRIPTION (provided by applicant): S6 kinase 1 (S6K1) is an important regulator of cell size control, protein translation and cell proliferation, and one of the best-characterized downstream targets of the mammalian Target of Rapamycin (mTOR). RPS6KB1, the gene encoding S6K1, is amplified in up to 30% of breast cancers. S6K1 is over expressed in the majority of cases with RPS6KB1 amplification. Over-expression of S6K1 correlates with poor prognosis in breast cancer patients. S6K1 also mediates rapamycin sensitivity of breast cancer cells. The specific aims are designed to provide a comprehensive assessment of the therapeutic potential of the S6K1 signaling pathway by identifying and characterizing downstream effectors of S6K1 in breast cancer cells. The specific aims of this proposal focus on the mechanism by which S6K1 controls cell proliferation by identifying breast cancer cell specific S6K1 effectors. In Aim 1, we propose a biochemical approach coupled with mass spectrometry for identification of novel substrates of S6K1. In Aim 2, we will characterize S6K1 substrate proteins, and will map rapamycin-sensitive phosphorylation sites. In Aim 3, we will study the role of S6K1 substrates in control of breast cell proliferation. The proposed work will facilitate subsequent development of new inhibitors of S6K1 and its downstream effectors in treatment of tumors with S6K1 amplification. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer death in women. Current chemotherapies are indiscriminate, have toxic side effects, and in 45% of patients do not prevent cancer progression or recurrence. The experiments described in this proposal will allow us to comprehensively evaluate the role of S6K1 as a breast cancer oncogene and its therapeutic potential in the treatment of this disease.