Deregulation of growth factor signaling has been assigned as a hallmark in cancer development and progression. Amplification of growth factor dependent ras and phosphatidylinositol-3-OH kinase (PI3K) pathways leads to the phosphorylation-dependent hyperactivation of Akt in breast cancer that has been shown to correlate with disease progression from abnormal hyperplasia to tumor invasion. Through the phosphorylation a diverse set of substrates Akt is engaged in regulation of cell survival, cell-cycle progression, cell growth, and cell metabolism. The Akt signaling is regulated by the phosphorylation of Akt on the hydrophobic Ser-473 site and it has been recently identified that this regulatory site on Akt is phosphorylated by mammalian Target of Rapamycin Complex 2 (mTORC2). While it is evident that the mTORC2-dependent hyperactivation of Akt is associated with breast cancer development, it is not entirely known how the mTORC2 signaling accommodates the up-regulation of Akt during tumorigenesis. Lack of such knowledge outlines the gap in our understanding of the growth factor signaling in cancer. The objective of this application is to study the mTORC2 signaling in breast cancer. The central hypothesis of this application is that during cellular transformation the mTORC2 signaling is up-regulated to activate the Akt pathway as an important step in breast tumorigenesis and its progression. Our hypothesis has been formulated on the basis of the strong preliminary data produced in our laboratory, having recently analyzed the mTORC2 components and its activity in breast cancer cells, primary human mammary epithelial cells, and also human breast tumor samples. We propose to test our central hypothesis and accomplish the objectives of this application by pursuing the following three specific aims:
Specific Aim 1 : Characterization of mTORC2: its kinase activity and regulation in breast cancer cells.
Specific Aim 2 : The identification and functional studies of the novel effectors of mTORC2.
Specific Aim 3 : The role of mTORC2 in breast cancer models in vivo. The proposed work is innovative, because the focus of this study is mTORC2, the recently identified mediator of growth factor signaling defined in our previous work as a regulatory kinase of Akt. This study will have an important positive impact, because mTORC2 as a crucial player in growth factor signaling with its enzymatic kinase activity attracts a great interest as a novel anti-cancer drug target.
The central hypothesis of this application is that during cellular transformation the mTORC2 signaling is up-regulated to activate the Akt pathway as an important step in development of primary breast cancer tumors. In this grant application we propose to study induction of mTORC2 in breast cancer, its regulation, and its role in breast tumorigenesis. The rationale for proposed research is that, once we know the regulatory mechanism of the mTORC2 complex by dissecting its up-stream and downstream regulators, this complex will become accessible target to pharmacological intervention with potential application to treat cancer.
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