title: Oncogenic suppression of apoptosis uncovers a Rac1/JNK proliferation pathway activated by loss of Par3.
abstract: Disruption of epithelial organization and loss of growth control are universal features of carcinomas, yet how these features are linked during cancer progression remains poorly understood. Cell polarity proteins control cellular and tissue organization and are emerging as important mediators of cancer progression. The Par3 polarity protein is a molecular scaffold that functions to recruit and spatially organize signaling factors, and was recently identified as a suppressor of breast cancer invasion and metastasis. Here, we show that loss of Par3 in mammary epithelial cells promotes apoptosis, and that oncogenic Notch overcomes the apoptotic signal to reveal an unexpected pro-proliferative role for loss of Par3 in mammary tumors. In this context, loss of Par3 deregulates Rac1 activity to activate Jun N-terminal Kinase-dependent proliferation and tumor growth. Thus, we demonstrate a mechanism by which loss of Par3 promotes proliferation and tumorigenesis, which supports a tumor-suppressive function for Par3 in the mammary epithelium.
authors.affiliation: Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Archibald
authors.affiliation: Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Mihai
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: I G
authors.initials: IG
authors.lastname: Macara
authors.affiliation: Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: L
authors.initials: L
authors.lastname: McCaffrey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics*; D018797:Cell Cycle Proteins; D016764:Cell Polarity / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D009479:Neuropeptides; C115084:Pard3 protein, mouse; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein
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