The role of integrin β5 in the TGF-β-mediated EMT in normal mammary epithelial and breast carcinoma cells
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Breast cancer is a life-threatening disease and the most commonly diagnosed cancer among women in the United States. While the detection of early lesions can ensure effective surgical/therapeutic intervention, advanced breast cancers are frequently incurable. Breast cancer progression and the development of metastasis have been linked to Tumor Growth Factor β (TGF-β) cytokines. TGF-β controls mammary development and homeostasis and acts as a potent tumor-suppressor in early-stage breast cancer. In advanced cancer, however, TGF-β has been implicated in invasion and metastasis through the induction of the Epithelial-Mesenchymal Transition (EMT), matrix degradation and angiogenesis. Thus, therapeutic inhibition of TGF-β may exhibit adverse effects. Studies from our laboratory have demonstrated that tropomyosin-stabilized actin stress fibers are critical for the TGF-β induction of EMT and cell-matrix adhesions, as well as tumor suppressor functions. We have also shown that actin fibers are required for integrin-mediated signaling during EMT. Little information is available regarding the role of specific integrin molecules in the TGF-β-induced EMT. We identified integrin β5 as a TGF-β-regulated adhesion protein, and the objective of this study was to establish the function of integrin β5 in the EMT process in response to TGF-β in non-tumorigenic mammary epithelial cells, as well as to determine integrin β5 functions in the oncogenic potential of breast cancer cells. Our work revealed that integrin β5 is an important mediator of the TGF-β-induced EMT: knock-down of integrin β5 blocked the EMT response to TGF-β, impairing the dissolution of tight junctions and the formation of specific cell-matrix adhesion structures in mouse and human mammary epithelial cell lines, and ablated the TGF-β induction of cell adhesiveness and integrin signaling. Our work also demonstrated a critical role of integrin β5 in the tumorigenic potential of breast carcinoma cells both in vitro and in vivo: we showed that integrin β5 engagement activates two independently-operating signaling pathways, SRC-FAK and MEK-ERK, both of which contribute to the tumorigenic capacity of carcinoma cells. Additionally, we identified a region in the integrin β5 intracellular domain as a major contributor in the integrin β5-mediated tumorigenic behavior of breast carcinoma cells. Finally, we identify zyxin as one of the molecular component of integrin β5-mediated cell-matrix adhesions and contributing significantly to actin cytoskeleton destabilization. These studies identified integrin β5 as a major contributor of the EMT process in response to TGF-β and of the tumorigenic potential of carcinoma cells. Integrin β5 may therefore serve as a suitable therapeutic target to inhibit TGF-β pro-tumorigenic functions without affecting its tumor-suppressor capabilities.