Cathespin D, a Marker for the Metastatic Potential of Breast Cancer, May Regulate the Mitogenic Activity of Fibroblast Growth Factor 1.

Fibroblast Growth Factor-1 (FGF-1) is a potent mitogen and angiogenic factor found in both normal and malignant tissues. FGF-1 mediates its diverse biological effects by binding to and activation of its high-affinity tyrosine kinase receptors, initiating a myriad of signaling cascades. Evidence indicates that the act of receptor engagement by the FGF ligand is insufficient for transduction of a full proliferative signal. it is speculated that FGF-FGFR internalization and its subsequent processing may play an active role in completing the mitogenic signal. The reported studies indicate that the FGF-1 mitogenic signal requires ligand endocytosis via the "classical" clathrin-mediated pathway and exposure to an acidic compartment. Furthermore, both a pepstatin- and leupeptin-sensitive event(s) appear critical for a full mitogenic response. Given the implicated role for a number of different proteases in contributing to the breast cancer pathology, this protease-sensitive activity in FGF-1 signaling is under investigation. FGF-1 has been reported to progress breast carcinomas from a hormone-dependent state to a hormone-independent state and from nonmetastatic to metastatic. Therefore, better understanding the mechanism of FGF-1 signaling could provide additional avenues for adjuvant therapies. An antimitogenic approach to treatment of breast cancer would have a broader efficacy, not limited by the hormone-responsive state of the tumor.