DECREASED TUMOR-FORMATION IN 7,12-DIMETHYLBENZANTHRACENE-TREATED STROMELYSIN-1 TRANSGENIC MICE IS ASSOCIATED WITH ALTERATIONS IN MAMMARY EPITHELIAL-CELL APOPTOSIS

To determine the role of a specific member of the metalloproteinase fa mily, stromelysin-1, in mammary carcinogenesis and tumor progression, transgenic mice expressing activated rat stromelysin-1 under the contr ol of the mouse mammary tumor virus promoter/enhancer were treated wit h the carcinogen 7,12-dimethylbenzanthracene (DMBA) to induce mammary tumors, Surprisingly, the expression of stromelysin-1 during the time of DMBA treatment reduced the number of mice developing mammary tumors , in particular adenoacanthomas, from 65 to 32% (P = 0.02), In contras t, when transgenic mice expressing both transforming growth factor alp ha and stromelysin-1 under the control of the mouse mammary tumor viru s long terminal repeat were treated with DMBA, there was no significan t difference in the number of mice that developed tumors compared to t ransforming growth factor alpha controls. A 4-fold increase in the num ber of apoptotic cells was detected in stromelysin-1 transgenic mice c ompared to littermate controls at the time of DMBA administration, sug gesting that the reduction in DMBA-induced tumorigenicity is likely to be due, at least in part, to an increased rate of cell turnover in st romelysin-1 transgenic mice, When malignant adenocarcinomas developed in the stromelysin-expressing mice, there was no detectable alteration in the extent of invasion or in the metastatic potential of these tum ors compared to tumors from control mice, These results suggest that t he expression of a single metalloproteinase, stromelysin-1, is insuffi cient for the progression of mammary adenocarcinomas to an invasive an d metastatic phenotype, but that matrix degradation by metalloproteina ses can alter basic processes of cell proliferation and apoptosis.