Interactions between cells and the extracellular matrix (ECM) are essential to the organization and maintenance of tissue architecture and function. ECM receptors serve as a link between the cell and the ECM. Through interactions with various matrix molecules and activation of intracellular signaling pathways, ECM receptors allow cells to sense and respond to their microenvironment. The matrix receptor dystroglycan (DG) has been shown to have roles in tissue morphogenesis including formation of

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... basement membranes, regulation of cell proliferation, differentiation and cell survival. DG is expressed in many tissues but has predominantly been studied in muscle. The function of dystroglycan within epithelia is currently unknown. To gain insight into the role of dystroglycan in the prostate epithelium, we generated individual prostate luminal cell (Probasin Cre) and basal cell (Keratin 5 Cre) specific DG knockout mice. DG was not required for maintenance of the basement membrane, epithelial polarity or cellular homeostasis in the prostate. Furthermore, gland morphology and ability to regenerate following androgen depletion were normal. These studies indicate DG may have more subtle roles within the epithelium. Disruption of cell/ECM interactions is a hallmark of cancer. DG expression is lost in many carcinomas including prostate, yet the molecular mechanism behind loss of expression and the functional consequences remain unclear. To elucidate the molecular mechanism in prostate cancer, we examined DG expression in metastatic prostate cancer cell lines. DG was heterogeneously glycosylated across the cell line panel. Surprisingly, we show that LARGE2 is able to functionally glycosylate DG and loss of LARGE2 expression is a mechanism for DG hypoglycosylation in prostate cancer. Additionally, 2 initial results suggest that oncogene expression modulates DG glycosylation status through regulation of LARGE2 expression. This work has shown a novel mechanism for DG hypoglycosylation in prostate cancer. In summary, these studies have contributed new information on the role of DG in the prostate epithelium. Furthermore, we have shown a novel mechanism for loss of DG glycosylation in prostate cancer and have provided initial data suggesting oncogene expression modulates DG glycosylation. These insights may lead to advances in the treatment of prostate cancer. Abstract Approved: ____________________________________ Thesis Supervisor ____________________________________