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.

BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo

“…Qualitative and quantitative alterations in O-and N-glycosylation in Integrins are consistent features of malignancies (32). Integrins promote various adhesion-dependent effects in tumor cells, including proliferation, survival, migration, and invasion through focal adhesion kinase (FAK) signaling cascades (33)(34)35). FAK phosphorylation is considered to be one of the initial steps that allows binding of Src and Fyn for further phosphorylation leading to signaling cascade (14,(36)(37)(38).…”

Integrin-β5 and zyxin mediate formation of ventral stress fibers in response to transforming growth factor β

“…3,8,20,21 In particular, integrin-β5 chain is required for TGF-β-induced EMT 8 and myofibroblast conversion. 22 Recent studies have also Integrin-β5 and zyxin mediate formation of ventral stress fibers in response to transforming growth factor β implicated integrin-β5 in the tumorigenic and metastatic capacities of breast carcinomas 23 and pancreatic cancer cells. 24 The cytoplasmic domain of integrins serves as an anchor for actin fibers and a platform for the assembly of adhesomes and adhesion-mediated signaling.…”

“…30 Accordingly, integrin-β5-FAK-Src signaling contributes to tumorigenic potential of breast cancer cells. 23 In addition, integrin-β1 may also contribute to actin remodeling in response to TGF-β by mediating p38MAPK signaling. 21 Thus, integrins can mediate cell-matrix adhesion and actin remodeling induced by TGF-β, although the function of specific β-integrins and the organization of the TGF-β-induced actin fiber structures remain to be defined.…”

PtdIns(3,4,5)P3-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) Activity Promotes Breast Cancer Cell Proliferation and Tumor Growth via Activation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Signaling

“…6, A and B). Previous studies have independently reported that ERK1/2 or PREX1/Rac1 promotes anchorage-independent growth of breast cancer cells (10,36,37). To determine whether PREX1 promotes anchorage independent colony formation via Rac1-ERK1/2, soft agar studies were undertaken in MDA-MB-231-luc-D3H1 cells overexpressing PREX1 in the presence of a MEK1/2 inhibitor (U0126), Rac1 inhibitor (NSC23766), or DMSO (vehicle).…”