Abstract SY07-02: Polarity proteins in morphogenesis and metastasis

Abstract

Abstract Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. A conserved set of polarity proteins, called PAR proteins, drives cell polarization in many contexts, and in Drosophila these proteins can function as tumor suppressors. However, to date, only Par4 (LKB1) has been implicated in human cancers. To determine whether other polarity proteins might have tumor suppressor functions in mammals, we have used lentiviruses to deliver oncogenes and shRNAs to primary murine mammary cells, which are then implanted into the cleared fat pads of isogenic host mice. Using this system, we silenced expression of the PAR3 polarity protein in the context of oncogenic Notch (NICD) or Ras. Depletion of Par3 dramatically reduced tumor latency in both models, producing tumors that were highly invasive and metastatic. Notably, the NICD/shPAR3 tumors retained epithelial character, with no evidence of epithelial-mesenchymal transition in either the primary tumors or the lung metastases. We have identified an unexpected signaling pathway that drives invasion in these tumors. Importantly, PAR3 protein expression is significantly reduced in ∼50% of human breast cancers, as compared to matched normal tissue. Together, these data provide a link between cell polarity, tissue organization, and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY07-02. doi:10.1158/1538-7445.AM2011-SY07-02