Integrin β5 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 alpha v-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 b5 using RNA interference and reexpression of integrin beta 5. Depletion of integrin b5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin b5 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.