Abstract B048: The role of mTORC2 in mammary morphogenesis and HER2-mediated tumorigenesis
Authors: Morrison Meghan M. , Brantley-Sieders Dana , Hicks Donna , Sanchez Violeta , Cook Rebecca 
Published: May 2015

Breast cancer is the most common malignancy among western women. Approximately 20% of breast cancers exhibit overexpression of 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 molecularly-targeted therapies often occurs, underscoring the need for increased understanding of the signaling pathways required for HER2-mediated transformation and tumor malignancy. As such, transformation by HER2 requires signaling through the phosphoinositide 3-kinase (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 also associated with extreme toxicity. Understanding factors both upstream and downstream of PI3K is necessary to improve patient morbidity and mortality and will allow us to understand the earliest events driving HER2-related tumorigenesis.

The serine/threonine kinase mammalian target of rapamycin (mTOR) controls key cellular processes, including growth, survival and metabolism. mTOR operates downstream and within the PI3K/Akt pathway within two structurally and functionally distinct complexes known as mTORC1 and mTORC2, whose activity and substrate specificity are regulated by complex-specific cofactors. Specifically, the protein Raptor is a required cofactor for the rapamycin-sensitive mTORC1 complex, which is activated downstream of PI3K/Akt and mediates cell growth and metabolism. The protein Rictor is a required cofactor 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. The clinical efficacy of rapamycin in luminal breast cancers underscores the importance of mTOR signaling in breast cancers and supports its role as an effector of PI3K. However, little is known about the distinct role of mTORC2 in breast cancer. Interestingly, emerging 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), leading us to hypothesize that mTORC2 drives PI3K/Akt-mediated cell survival of normal and HER2-transformed breast epithelial cells. We show that loss of Rictor/mTORC2 decreases three-dimensional growth, survival, migration and phosphorylation of Akt (S473) in HER2-positive breast cancer cells and HER2-transformed MCF10A mammary epithelial cells. Additionally, Rictor loss sensitizes HER2-positive breast cancer cells to the HER2 inhibitor, lapatinib. These and additional results from in vivo studies would support investigations into novel treatment combinations to improve the outcome for patients with HER2-amplified breast cancers.

Impact: mTORC2 remains understudied in breast cancers. 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. Because HER2 is overexpressed in nearly 20% of all breast cancers, these findings will impact a significant number of patients.

Citation Format: Meghan M. Morrison, Dana Brantley-Sieders, Donna Hicks, Violeta Sanchez, Rebecca Cook. The role of mTORC2 in mammary morphogenesis and HER2-mediated tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B048.