Abstract
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 deletion. Surprisingly, Akt re-activation was not sufficient to rescue cell survival or invasion, and modestly increased branching of mTORC2-impaired mammary epithelial cells (MECs) in culture and in vivo. However, another mTORC2 substrate, protein kinase C (PKC)-alpha, fully rescued mTORC2-impaired MEC branching, invasion, and survival, as well as branching morphogenesis in vivo. PKC-alpha-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary epithelial development during puberty, revealing a novel role for Rictor/mTORC2 in MEC survival and motility during branching morphogenesis through a PKC-alpha/Rac1-dependent mechanism.
Highlights
Post-natal mammary epithelial morphogenesis is a complex process during which an extensively branched ductal network develops from a rudimentary epithelial bud [1]
We assessed the role of mTORC1 and mammalian target of rapamycin (mTOR) complex 2 (mTORC2) complexes in normal mammary epithelial cell branching, survival, and invasion
Our studies identify a novel role for the mTORC2 complex in mammary morphogenesis, including cell survival and motility, which are relevant to breast cancer progression
Summary
Post-natal mammary epithelial morphogenesis is a complex process during which an extensively branched ductal network develops from a rudimentary epithelial bud [1]. Branching morphogenesis is most active during puberty and is regulated by endocrine hormones and local paracrine interactions with mesenchymal stroma [2]. In response to hormonal and growth factor cues, mammary epithelial cells (MECs) within the terminal end buds (TEBs), the club-shapes structures at the distal epithelial tips [1, 2], proliferate and collectively invade surrounding stroma. Differentiation of epithelial progenitors in the TEB populates the ducts with mature luminal MECs, and apoptosis canalizes the lumen. TEB bifurcation results from mechanical restraints at the TEB midline, forming new primary ducts. The dynamic processes that occur during puberty in the mammary epithelium are carefully coordinated by many molecular signaling pathways
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