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Loss of epithelial cell polarity is often associated with the development of carcinoma. Polarized MDCK cells and MCF-10A mammary epithelial cells grown in 3D are useful model systems to study the regulation of cell polarity in vitro and to investigate the interaction of oncogenes and cell polarity proteins. Using these experimental models, we have previously demonstrated that activation of the oncogene ErbB2 disrupts apical-basal polarity in mammary epithelial cells. Activated ErbB2 associates with the Par6-aPKC polarity complex and the interaction between Par6 and aPKC is indispensible for ErbB2-mediated disruption of cell polarity and inhibition of apoptosis. Following ErbB2 activation, we find a decrease in Par6-associated aPKC kinase activity. Furthermore, kinase dead aPKC cooperates with activated ErbB2 to transform mammary epithelial cells in vitro, without inducing any changes in proliferation of cells grown on plastic dishes. Taken together, our data implicate a target (or targets) of aPKC as a likely determinant of ErbB2-mediated disruption of cell polarity and transformation. Identification of these substrates could lead to the development of novel biomarkers to monitor the progression of ErbB2 positive tumors. 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 4042. doi:10.1158/1538-7445.AM2011-4042