Cancer is a progressive disease. We now know that accumulation of mutations, presence of high proliferation rates, adaptaion to stress conditions and loss of differentiation are some of the properties associated with cancer progression. While the pathways that drive cell proliferation are becoming increasingly clear, less is understood about how differentiation status is altered during cancer progression.

Cell polarity proteins regulate asymmetric distribution of proteins within cells and regulate morphogenesis and differentiation of progenitor cells in flies and worms. However, very little is known about the role that cell polarity proteins play during morphogenesis and differentiation in mammals. Furthermore, the role that cell polarity proteins play during initiation and progression of cancer is unclear. Research in my laboratory is aimed at understanding how cell polarity proteins regulate differentiation of progenitor cells, tissue morphogenesis and initiation and progression of cancer.

Recent studies from our laboratory have yielded surprising insights into the role that cell polarity proteins play in cancer. We find that the oncogenic receptor tyrosine kinase ErbB2/HER2 interacts with and inactivates cell polarity proteins to disrupt apical-basal polarity and to transform three-dimensional tissue-like structures generated by polarized breast epithelial cells. The ability of ErbB2/HER2 to disrupt cell polarity is independent of its ability to induce cell proliferation, suggesting that pathways that regulate cell polarity and cell proliferation can be uncoupled from each other. More recently, we demonstrated that disruption of polarity pathways deregulates morphogenesis of mammary epithelial cells in culture and cooperates with oncogenes to initiate carcinoma in animal models. These observations identify polarity proteins either as an initiating or as a cooperating event during the genesis of carcinoma and provide direct evidence for a role for polarity pathways during tumorigenesis. Thus, cell polarity proteins and the pathways they regulate are a novel class of targets that can be exploited for diagnosis and treatment of carcinoma.

Moving forward, research in my laboratory is broadly focused on investigating the role played by polarity proteins both during normal development and during initiation and progression of cancer. We are interested in: 1) identifying polarity pathways that are altered in breast and other cancers and determining their clinical relevance; 2) determining how polarity proteins control differentiation of progenitor cells; 3) developing mouse models with alterations in polarity genes to study both normal development and cancer progression; and 4) performing proteomics and genetic screens to identify ways to target the altered/rewired polarity pathways in cancer cells.

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