Bone morphogenetic proteins (BMPs) are multifunctional cytokines that elicit pleiotropic effects on biological processes such as cell proliferation, cell differentiation and tissue morphogenesis. With respect to cell proliferation, BMI's can exert either mitogenic or anti-mitogenic activities, depending on the target cells and their context. Here. we report that in low-density cultures of immortalized mammary epithelial cells, BMP-4 did not stimulate cell proliferation by itself. However, when added in combination with suboptimal concentrations of fibroblast growth factor (FGF)-2, FGF-7, FGF-10, epidermal growth factor (EGF) or hepatocyte growth factor (HGF), BMP-4 potently enhanced growth factor-induced cell proliferation. These results reveal a hitherto unsuspected interplay between BMP-4 and growth factors in the regulation of mammary epithelial cell proliferation. We Suggest that the ability of BMP-4 to potentiate the mitogenic activity Of Multiple growth factors may contribute to mammary gland ductal morphogenesis as well as to breast cancer progression. (C) 2008 Elsevier Inc. All rights reserved.