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 t he established role of urokinase plasminogen activator (uPA) and its recept or (uPAR) in invasion, this study was undertaken to explore the role of her egulin-beta1 in regulating uPA and uPAR in breast cancer invasion. The stim ulation by heregulin-beta1 of noninvasive human breast cancer MCF-7 cells i nduced the expression of uPA mRNA, protein, and its plasminogenic activity. This uPA mRNA expression was blocked by a transcriptional inhibitor, actin omycin D, and does require de novo protein synthesis for its optimal induct ion in MCF-7 cells, but not in mouse mammary epithelial HC11 cells. Heregul in-beta1 also induced the expression of uPAR mRNA and protein in an actinom ycin D-sensitive manner and cycloheximide superinduced the uPAR mRNA. Hereg ulin-beta1-stimulated signaling initiated the transcription from uPA- and u PAR-promoters. These results suggest that heregulin-beta1 regulation of bre ast cancer cell invasion may be mediated in part through the up-regulation of uPA and uPAR.