title: 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. 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 the 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 reexpression of integrin β5. Depletion of integrin β5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin β5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of vascular endothelial growth factor-A in integrin β5-depleted tumors. Tumor cells deficient in integrin β5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin β5 mediates the Src-focal adhesion kinase and MEK-extracellular signal-regulated kinase 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.
authors: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: A
authors: A
authors: Bianchi-Smiraglia
authors: S
authors: S
authors: Paesante
authors: A V
authors: AV
authors: Bakin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D039661:Integrin beta3 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D039641:Integrin beta Chains; D039661:Integrin beta3; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C084344:integrin beta5; C072170:integrin beta6; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases