Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways

Abstract

Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell adhesion receptors that mediate interactions of cells with extracellular matrix (ECM). The αv-β-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 development of therapeutic approaches targeting integrins. The study investigated the role of integrin β5 in breast carcinomas by depleting integrin β5 using RNA interference and re-expression of integrin β5. Depletion of integrin β5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth, and tumor angiogenesis, while re-expression of integrin β5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of VEGF-A in integrin β5-depleted tumors. Tumor cells deficient for integrin β5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin β5 mediates Src-FAK and MEK-ERK signaling events that operate independently, and inhibition of these pathways phenocopies integrin β5-deficiency. Breast carcinoma cells express high levels of integrin β5, whereas expression of integrin β3 is limited to stromal compartments and integrin β6 is lost in metastatic cells. Together these findings show a critical role for integrin β5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin β5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies.