Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor knock-out. Surprisingly, Akt re-activation was insufficient to rescue survival, branching, or motility of mTORC2-impaired mammary epithelial cells (MECs). However, activation of the mTORC2 substrate protein kinase C (PKC)-α fully rescued branching, invasion, and survival of MECs after genetic or pharmacological mTORC2 inhibition. PKCα-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary morphogenesis, revealing a novel role for Rictor/mTORC2 in survival and motility of untransformed MECs through an Akt-independent, PKCα/Rac1-dependent mechanism.

Citation Format: Meghan M. Morrison, Christian D. Young, Shan Wang, Violeta M. Sanchez, Cook S. Rebecca, Donna J. Hicks, Dana M. Brantley-Sieders. mTORC2 directs breast morphogenesis through Rictor-dependent PKCα/Rac1 signaling independent of Akt. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B49.