Abstract P1-04-02: The role of the mTORC1/S6K1 signaling pathway in ER-positive breast cancer.

Abstract

Abstract The mammalian target of rapamycin complex 1 (mTORC1) is a central signaling node in mediating cellular responses to mitogens, hormones and nutrients. The 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt, RSK and many others. S6K1 is the principal kinase effector downstream mTORC1. S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels, and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis, and cell migration and invasion. Growing evidence indicates that there exists a close interaction between the mTORC1/S6K1 pathway and estrogen receptor (ER) signaling. Notably, endocrine resistance is often associated with ligand-independent activation of ERα signaling due to hyperactivation of the mTORC1 signaling pathway, and can be reversed by the mTORC1 inhibitor everolimus in vitro. Several lines of evidence suggest an important role for S6K1 in ER-positive breast cancer. We demonstrated that S6K1 directly phosphorylates ERα on Ser167, leading to activation of its transcriptional activity. While the MAPK-regulated p90 RSK also contributes to phosphorylation of this site, its contribution is early and transient, while the phosphorylation of Ser167 by S6K1 is prolonged and sustained. Intriguingly, we also found that S6K1 expression is estrogenically regulated. This regulation involves the transcription factor GATA-3 and others. Thus it appears that S6K1 expression is maintained in two modes: a basal level of expression, typical of normal cells, and an estrogen/ERα-dependent specific upregulation. Therefore, there exists a feed-forward regulatory loop whereby S6K1 activates ERα transcriptional activity, leading to increased expression of S6K1. This finding is of great interest since it not only sheds light on the mode of transcriptional regulation of S6K1 expression, but may help understand the role of S6K1 overexpression and activation in the development and progression of breast cancer. Therefore, hyperactivation of mTORC1/S6K1 signaling may be closely related to ER-positive status in breast cancer, and may be utilized as a marker for prognosis and a therapeutic target. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-02.