Abstract A118: The mTORC2 component Rictor directs branching morphogenesis and survival in the mammary epithelium

Abstract

Abstract The intracellular serine/threonine kinase mTOR functions in two distinct complexes that integrate many cellular cues to regulate diverse processes in development and disease. Raptor-dependent mTOR Complex-1 (mTORC1) mediates cell growth and metabolism, whereas the less well-studied Rictor-dependent mTOR Complex-2 (mTORC2) promotes cell survival and cytoskeletal organization. Previous studies link mTORC1 to malignant transformation of mammary epithelial cells (MECs). The role of mTOR and the relative contributions of mTORC1 versus mTORC2 in postnatal mammary morphogenesis, however, remain unclear. We report that mTORC2 ablation via Rictor loss impaired branching morphogenesis, MEC survival, MEC migration, and mTORC2-mediated signaling through Akt and Rac1-GTPase in vivo and ex vivo. Constitutively active Rac1 (CA-Rac1) rescued branching, invasion, and survival of mTORC2-impaired MECs, but CA-Akt did not. These effects were recapitulated by rapamycin treatment. Surprisingly, genetic mTORC1 disruption via Raptor gene targeting did not affect ascinar mammary morphogenesis in organoids or in vivo, but did cause decreased signaling through the mTORC1 effector ribosomal protein S6 and transiently slowed cellular proliferation. These data demonstrate the distinct, non-overlapping properties of mTORC1 and mTORC2 during post-natal mammary development, roles which may be preserved in breast cancers. Citation Format: Meghan M. Morrison, Donna Hicks, Rebecca S. Cook, Dana M. Brantley-Sieders. The mTORC2 component Rictor directs branching morphogenesis and survival in the mammary epithelium. [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 A118.