RESUMO
Transforming growth factor-ß (TGF-ß) is an important regulator of breast cancer progression. However, how the breast cancer microenvironment regulates TGF-ß signaling during breast cancer progression remains largely unknown. Here, we identified fibulin-3 as a secreted protein in the breast cancer microenvironment, which efficiently inhibits TGF-ß signaling in both breast cancer cells and endothelial cells. Mechanistically, fibulin-3 interacts with the type I TGF-ß receptor (TßRI) to block TGF-ß induced complex formation of TßRI with the type II TGF-ß receptor (TßRII) and subsequent downstream TGF-ß signaling. Fibulin-3 expression decreases during breast cancer progression, with low fibulin-3 levels correlating with a poorer prognosis. Functionally, high fibulin-3 levels inhibited TGF-ß-induced epithelial-mesenchymal transition (EMT), migration, invasion and endothelial permeability, while loss of fibulin-3 expression/function promoted these TGF-ß-mediated effects. Further, restoring fibulin-3 expression in breast cancer cells inhibited TGF-ß signaling, breast cancer cell EMT, invasion and metastasis in vivo. These studies provide a novel mechanism for how TGF-ß signaling is regulated by the tumor microenvironment, and provide insight into targeting the TGF-ß signaling pathway in human breast cancer patients.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Proteínas da Matriz Extracelular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/genéticaRESUMO
The type III TGF-ß receptor (TßRIII) is a ubiquitous co-receptor for TGF-ß superfamily ligands with roles in suppressing cancer progression, in part through suppressing cell motility. Here we demonstrate that TßRIII promotes epithelial cell adhesion to fibronectin in a ß-arrestin2 dependent and TGF-ß/BMP independent manner by complexing with active integrin α5ß1, and mediating ß-arrestin2-dependent α5ß1 internalization and trafficking to nascent focal adhesions. TßRIII-mediated integrin α5ß1 trafficking regulates cell adhesion and fibronectin fibrillogenesis in epithelial cells, as well as α5 localization in breast cancer patients. We further demonstrate that increased TßRIII expression correlates with increased α5 localization at sites of cell-cell adhesion in breast cancer patients, while higher TßRIII expression is a strong predictor of overall survival in breast cancer patients. These data support a novel, clinically relevant role for TßRIII in regulating integrin α5 localization, reveal a novel crosstalk mechanism between the integrin and TGF-ß superfamily signaling pathways and identify ß-arrestin2 as a regulator of α5ß1 trafficking.