Investigating the Role of Paxillin in Mammary Gland Morphogenesis and Breast Cancer Progression
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AbstractBreast cancer is one of the most invasivecancers among women. Understanding the mechanisms contributing to breast cancer progression may identify potential ways to prevent and cure the disease. Meanwhile, mammary gland morphogenesis shares similar mechanisms to allow the ducts to invade and occupy the fat pad. Thus, it is equally important to investigate the normal mammary gland development as breast tumor progression. Paxillin, as a focal adhesion scaffold protein, has previously been implicated in multiple types of cancer cell migration and invasion through its role in cell-ECM signaling. Herein, I utilized a novel paxillin conditional knockout mouse model and paxillin knockout mouse crossed with PyMT breast tumor mouse model to show that paxillin is critical for both mammary gland morphogenesis and breast tumor progression. In Chapter 2, by evaluating the developing mammary gland morphology with immunohistochemistry and the three-dimensional cultured mammary organoids and acini, a critical role of paxillin was shown in facilitating apical-basal polarity formation in the luminal epithelial cells in part, through its control of HDAC6 activity and associated microtubule acetylation. Correct polarization and columnar shape of the epithelial cells potentially contributes to lumen formation and branching of the ducts. Investigation in Chapter 3 highlights a crucial role of paxillin in breast cancer invasion and distant organ metastasis, but did not affect the primary tumor growth rate. Further analysis revealed that paxillin is required for the endocytosis and recycling of E-cadherin, which is important for the maintenance of Adherens junction equilibrium during cancer cell collective migration. This thesis characterizes the roles for paxillin in mammary gland morphogenesis and breast cancer progression and reveals the importance of paxillin-dependent apical trafficking in normal epithelial cells, and E-cadherin trafficking in collective migrating tumor cells. Together, this work highlights a trafficking-dependent mechanism for paxillin during both physiologic and pathologic processes in the mammary gland.
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