Heregulin regulation of urokinase plasminogen activator and its receptor: human breast epithelial cell invasion.

Heregulin-beta1, which binds human epidermal growth factor receptors 3 and 4, promotes motility and invasiveness of breast cancer cells. Considering the established role of urokinase plasminogen activator (uPA) and its receptor (uPAR) in invasion, this study was undertaken to explore the role of heregulin-beta1 in regulating uPA and uPAR in breast cancer invasion. The stimulation by heregulin-beta1 of noninvasive human breast cancer MCF-7 cells induced the expression of uPA mRNA, protein, and its plasminogenic activity. This uPA mRNA expression was blocked by a transcriptional inhibitor, actinomycin D, and does require de novo protein synthesis for its optimal induction in MCF-7 cells, but not in mouse mammary epithelial HC11 cells. Heregulin-beta1 also induced the expression of uPAR mRNA and protein in an actinomycin D-sensitive manner and cycloheximide superinduced the uPAR mRNA. Heregulin-beta1-stimulated signaling initiated the transcription from uPA- and uPAR-promoters. These results suggest that heregulin-beta1 regulation of breast cancer cell invasion may be mediated in part through the up-regulation of uPA and uPAR.