Abstract Maintenance of cell polarity and tissue architecture are essential in preventing neoplasia. Three different protein complexes control cellular polarity, including the Par3/aPKC/Par6 complex, the Crumbs/Pals/Patj complex and the Scribble/Dlg/Lgl complex. Of these, only the loss of Lgl promotes massive tissue growth and cellular migration in Drosophila as well as altered cellular polarity. Humans have two well-conserved homologs, Hugl1 and Hugl2. Expression of Hugl1 is downregulated, lost, or mutated in many cancers, including colorectal, endometrial, hepatocellular carcinoma, malignant melanomas, and breast cancer. We have previously examined the role of Hugl1 and Hugl2 in breast epithelial cells and found that Hugl1 loss results in a failure of growth control, gain of mesenchymal phenotypes, and a loss of both apicobasal and planar polarity. We have now determined that these phenotypes represent a fundamental change in cellular differentiation and that loss of Hugl1 results in cellular transdifferentiation. Loss of Hugl1 expression in breast epithelial cells results in the induction of a mixed-phenotype population (composed of CD44high/CD49flow and CD44low/CD49fhigh), whose growth and migration are driven by the Epidermal Growth Factor Receptor (EGFR). These populations exhibit increased anchorage-independent growth and form soft agar colonies in an EGF-dependent manner, and these behaviors are selectively enhanced in the CD44high/CD49flow population. Hugl1 loss results in the mislocalization of EGFR, resulting in TAZ and SLUG nuclear translocation. Together, these data indicate that when Hugl1 is lost in normal epithelial cells, polarity loss is accompanied by a transdifferentiation and increased anchorage-independent growth and migration. Citation Format: Erin Greenwood, David Ebertz, Anthony Fabiano, Joyce A. Schroeder. Loss of Hugl1 induces an EGF-dependent cellular transdifferentiation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A16.