Breast cancer is the most common malignancy among western women. Approximately 20% of breast cancers overexpress human epithelial growth factor receptor 2 (HER2), a marker of aggressive disease. While HER2-targeted therapies have improved patient survival in this subset, resistance to these therapies often occurs, underscoring the need for increased understanding of the signaling pathways required for HER2-mediated transformation. As such, HER2 transformation requires signaling through the PI3K/Akt signaling cascade, that regulates cell growth/survival, metabolism and motility. While targeting PI3K/Akt in HER2-positive breast cancers has been met with some clinical success, it is associated with extreme toxicity. Understanding factors both upstream and downstream of PI3K is necessary to improve patient morbidity and mortality. The serine/threonine kinase mammalian target of rapamycin (mTOR) operates downstream and within the PI3K/Akt pathway within two distinct complexes known as mTORC1 and mTORC2, whose activity are regulated by complex-specific cofactors. Specifically, the protein Raptor is required for the mTORC1 complex, which mediates cell growth and metabolism. The protein Rictor is required for mTORC2, which controls cell survival, polarity, and cytoskeletal dynamics. mTORC2 supports Akt activation through direct phosphorylation on S473, which is necessary for maximal PI3K/Akt signaling. While most studies of mTOR in breast cancer have focused on mTORC1, little is known about the distinct role of mTORC2 in breast cancer. Interestingly, evidence from prostate and glioblastoma models suggest a direct link between mTORC2 and PI3K-driven cancer progression. Our preliminary data shows that loss of Rictor/mTORC2, but not Raptor/mTORC1, in primary mammary epithelial cells (PMECs) impairs branching morphogenesis, proliferation, survival and phosphorylation of Akt (S473). Additionally, we have shown that genetic loss of Rictor in HER2- positive breast cancer cells impairs cell migration and survival. Herein, we will test the hypothesis that mTORC2 drives PI3K/Akt-mediated cell survival of normal and HER2-transformed breast epithelial cells. We will use genetic models in culture and in vivo to determine: how loss of mTORC2 affects post-natal mammary epithelial morphogenesis (Aim 1) and spontaneous HER2-driven tumor formation (Aim 2). We will assess the therapeutic implications of mTORC2 inhibition (alone and in combination with clinically relevant HER2 inhibitors) in HER-driven human breast cancer cells (Aim 3). This study will be the first to examine the role of mTORC2 in mammary morphogenesis and in HER2-transformed breast cancers, providing unprecedented knowledge and mechanistic understanding of mTORC2 in breast cancers.
The protein Rictor is a required cofactor for the mTORC2 complex, which controls cell survival, polarity and cytoskeletal dynamics. We have shown that loss of Rictor/mTORC2 impairs migration and survival of HER2-positive breast cancer cells. This study will be the first to examine the role of mTORC2 in mammary morphogenesis and HER2-mediated tumorigenesis, providing unprecedented knowledge and mechanistic understanding of mTORC2 in breast cancers.
| Williams, Michelle M; Lee, Linus; Hicks, Donna J et al. (2017) Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade. Mol Cancer Res 15:259-268 |
| Morrison Joly, Meghan; Hicks, Donna J; Jones, Bayley et al. (2016) Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers. Cancer Res 76:4752-64 |
