Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis

The interaction between the erbB tyrosine kinase receptors and their ligand s plays an important role in tumor growth via the regulation of autocrine a nd paracrine loops. We report the effect of heregulin beta 1, the ligand fo r erbB-3 and erbB-4 receptors, on the regulation of vascular endothelial gr owth factor (VEGF) expression, using a panel of breast and lung cancer cell lines with constitutive erbB-2 overexpression or engineered to stably over express the erbB-2 receptor. We demonstrate that heregulin beta 1 induces V EGF secretion in most cancer cell lines, while no significant effect was ob served in normal human mammary and bronchial primary cells. Overexpression of erbB-2 receptor results in induction of the basal level of VEGF and expo sure to heregulin further enhances VEGF secretion. This is associated with increased VEGF mRNA expression. In contrast, VEGF induction is significantl y decreased in a T47D cell line where erbB-2 is functionally inactivated. C onditioned media from heregulin-treated cancer cells, but not from normal c ells, stimulates endothelial cell proliferation; this paracrine stimulation is inhibited by co-exposure to a specific VEGF neutralizing antibody, Furt hermore, heregulin-mediated angiogenesis is observed in the in vivo CAM ass ay. This study reports the first evidence of VEGF regulation by heregulin i n cancer cells.