title: mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis.
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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Morrison
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Young
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Tammy
authors.initials: T
authors.lastname: Sobolik
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Violeta M
authors.initials: VM
authors.lastname: Sanchez
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Hicks
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley-Sieders
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005260:Female; D008321:Mammary Glands, Animal / Q000196:embryology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics* / Q000502:physiology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051571:Protein Kinase C-alpha; D020830:rac1 GTP-Binding Protein