Heregulin regulation of autocrine motility factor expression in human tumor cells

The exposure of cells to growth factors has been shown to induce cytoskeleton reorganization, leading to stimulation of cell motility and invasion. Heregulin beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 and human epidermal growth factor receptor 4 receptors, is a regulatory secretory polypeptide with a distinctive function in promoting motility and invasiveness of breast cancer cells. In addition to HRG, motility and invasiveness of tumor cells may also involve up-regulation of expression and function of the autocrine motility factor (AMF). Here we explored the possible involvement of AMF in the motility-promoting action of HRG in the MCF-7 breast cancer cell model system. We report that HRG increases the expression of AMF mRNA by 3-8-fold in an actinomycin D-sensitive manner and does not require de novo protein synthesis. The HRG-induced stimulation of AMF expression was inhibited by specific inhibitors of p42/44MAPK and p38MAPK kinases, but not by an inhibitor of the phosphatidylinositol 3'-kinase pathway. Other HRG-responsive human cell lines demonstrated that HRG does indeed significantly up-regulate AMF expression. Furthermore, HRG-stimulated increased motility was partially suppressed by inclusion of an anti-AMF antibody to breast cancer cells, suggesting that a HRG-mediated increase in cell motility may be mediated, at least in part, via induction of AMF. The present study is the first demonstration of AMF regulation by a growth factor and suggests a potential role for AMF in HRG regulation of breast cancer cell motility and a novel function of HRG as a regulator of motility factor expression.