title: Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis.
abstract: Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. To address this issue, we depleted the Par3 polarity gene by RNAi in combination with oncogenic Notch or Ras(61L) expression in the murine mammary gland. Par3 silencing dramatically reduced tumor latency in both models and produced invasive and metastatic tumors that retained epithelial marker expression. Par3 depletion was associated with induction of MMP9, destruction of the extracellular matrix, and invasion, all mediated by atypical PKC-dependant JAK/Stat3 activation. Importantly, Par3 expression is significantly reduced in human breast cancers, which correlates with active aPKC and Stat3. These data identify Par3 as a regulator of signaling pathways relevant to invasive breast cancer.
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, Department of Oncology, McGill University, Montreal H3A 1A3, Canada. luke.mccaffrey@mcgill.ca
authors.forename: Luke Martin
authors.initials: LM
authors.lastname: McCaffrey
authors.forename: JoAnne
authors.initials: J
authors.lastname: Montalbano
authors.forename: Constantina
authors.initials: C
authors.lastname: Mihai
authors.forename: Ian G
authors.initials: IG
authors.lastname: Macara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; C115084:Pard3 protein, mouse; D011493:Protein Kinase C; D020780:Matrix Metalloproteinase 9; D016283:Proto-Oncogene Proteins p21(ras)