RESUMEN
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-ß-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 ß5 in breast carcinomas by depleting integrin ß5 using RNA interference and reexpression of integrin ß5. Depletion of integrin ß5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin ß5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of vascular endothelial growth factor-A in integrin ß5-depleted tumors. Tumor cells deficient in integrin ß5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin ß5 mediates the Src-focal adhesion kinase and MEK-extracellular signal-regulated kinase signaling events that operate independently, and inhibition of these pathways phenocopies integrin ß5 deficiency. Breast carcinoma cells express high levels of integrin ß5, whereas expression of integrin ß3 is limited to stromal compartments and integrin ß6 is lost in metastatic cells. Together, these findings show a critical role for integrin ß5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin ß5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies.
Asunto(s)
Neoplasias de la Mama/metabolismo , Cadenas beta de Integrinas/metabolismo , Sistema de Señalización de MAP Quinasas , Metástasis de la Neoplasia/genética , Animales , Adhesión Celular , Línea Celular , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Cadenas beta de Integrinas/biosíntesis , Cadenas beta de Integrinas/genética , Integrina beta3/biosíntesis , Glándulas Mamarias Humanas/citología , Ratones , Ratones SCID , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neovascularización Patológica/genética , Interferencia de ARN , ARN Interferente Pequeño , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
The impact of calcium signaling on many cellular functions is reflected by the tight regulation of the intracellular Ca(2+) concentration that is ensured by diverse pumps, channels, transporters and Ca(2+) binding proteins. In this review, we present recently identified novel sarco(endo)plasmic reticulum proteins that may have a potential involvement in the regulation of Ca(2+) homeostasis in striated muscles.