Loss of the Par3 Polarity Protein Promotes Breast Tumorigenesis and Metastasis

SummaryLoss 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 Ras61L 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.

► Par3 protein expression is significantly reduced in human breast cancers
► Loss of Par3 cooperates with oncogenes to trigger rapid tumor growth and metastasis
► Loss of Par3 enhances oncogene-dependent invasion in the absence of overt EMT
► Atypical PKC-dependent activation of Stat3 is essential for increased invasiveness