Role of Heregulin in the Neovascularization of Breast Carcinoma Cancer

摘要

Several oncogenese, growth factors, hormones and hypoxia have been shown to up-regulate VEGF, an essential angiogenia factor for the progression of breast carcinomas. The angiogenic factor CYRG1, a ligand for the alphavbeta3 integrin is differentially up-regulated in invasive and metastatic breast cancer cells overexpressing the epidermal growth factor-like growth factor Heregulin (HRG). HRG can regulate breast cancer neovascularization through its ability to activitie the expression and secretion of VEGF. Although CYR61 is thought to be an angiogenic ligand for alphavbeta3 integrin in endothelial cells, little is know about the regulatory role of CYR61 on the secretion of VEGF in the epithelial compartment of breast carcinoma. We speculated that CYR61 may promote VEGF-dependent breast cancer angiogensis in an autocrine fashion, and we examined whether HRG-induced over-secretion of VEGF in breast cancer cells associated with an increased CYR61-regulated alpha4beta3 integrin signaling. First constitutive VEGF secretion positively correlated with HRG overexpression, but not with HER-2/neu (erbB-2) oncogene status, in a panel of human breast cancer cell lines. Second, we evaluated the levels of VEGF secretion in MDA-231 cells, a natural breast cancer model overexpressing HRG. In which HRG expression was diminished using an HRG antisense (AS) cDNA. Secretion of VEGF was significantly diminished in the unselected MDA-MB-231/AS- POOL population (up to 30% reduction), and decreased by about 55% in MDA-231/AS- 31 transfectants, an AS-HRG clone expressing low to undetectable levels of HRG.