Matrix Dependent Mechanisms Involved in Tumor Promotion in Initiated Human Mammary Epithelium by Reactive Stroma

Abstract : Matrix metalloproteinases (MMPs) are thought to play important regulatory roles in normal development and disease. In addition to their established role in tumor invasion and metastasis, recent studies using mice that overexpress or lack specific MMPs or their inhibitors indicate that several MMPs can influence early tumor development. Our data indicate that stromal MMPs play an important role in tumor establishment. The coinjection of mouse embryo fibroblasts (MEFs) fosters human breast carcinoma cell growth in nude mice, whereas isogenic MEPs lacking either MMP-2 (gelatinase-A) or MMP-3 (stromelysin-I), but not MMP-9 (gelatinase-B), are deficient in their ability to foster this growth. This occurs even though the tumor cells and the murine hosts retain the ability to express these genes. This supports the emerging thesis that stromal signals and enzymes are an important factor in early tumor development. In addition, MMP-2 and MMP-3 are upregulated and activated during normal pubertal branching morphogenesis of the murine mammary gland. Transgenic mice that overexpress MMP-3 in mammary gland show increased ductal branching and mice null for MMP-3 show significantly diminished branching, whereas mice lacking MMP-2 have retarded ductal elongation. Thus MMP-2 and MMP-3 play critical roles in both tumor development and normal mammary gland morphogenesis.