Integrin [beta]5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways

Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell-adhesion receptors that mediate interactions of cells with extracellular matrix. The αv-[beta]-family of integrins contributes to tumorigenesis, response to therapy and cancer stem cell biology. Thus, understanding the function of specific integrins in cancer is critical for the development of therapeutic approaches targeting integrins. The study investigated the role of integrin [beta]5 in breast carcinomas by depleting integrin [beta]5 using RNA interference and reexpression of integrin [beta]5. Depletion of integrin [beta]5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin [beta]5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of vascular endothelial growth factor-A in integrin [beta]5-depleted tumors. Tumor cells deficient in integrin [beta]5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin [beta]5 mediates the Src-focal adhesion kinase and MEK-extracellular signal-regulated kinase signaling events that operate independently, and inhibition of these pathways phenocopies integrin [beta]5 deficiency. Breast carcinoma cells express high levels of integrin [beta]5, whereas expression of integrin [beta]3 is limited to stromal compartments and integrin [beta]6 is lost in metastatic cells. Together, these findings show a critical role for integrin [beta]5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin [beta]5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies. [PUBLICATION ABSTRACT]