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Decreased Tumor Formation in 7,12-Dimethylbenzanthracene-treated Stromelysin-1 Transgenic Mice Is Associated with Alterations in Mammary Epithelial Cell Apoptosis¹

Departments of Cell Biology [J. P. W., T. L., L. M. M.] and Medicine [R. J. C.], Vanderbilt University, Nashville, Tennessee 37232

To determine the role of a specific member of the metalloproteinase family, stromelysin-1, in mammary carcinogenesis and tumor progression, transgenic mice expressing activated rat stromelysin-1 under the control of the mouse mammary tumor virus promoter/enhancer were treated with 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 contrast, when transgenic mice expressing both transforming growth factor and stromelysin-1 under the control of the mouse mammary tumor virus long terminal repeat were treated with DMBA, there was no significant difference in the number of mice that developed tumors compared to transforming growth factor controls. A 4-fold increase in the number of apoptotic cells was detected in stromelysin-1 transgenic mice compared to littermate controls at the time of DMBA administration, suggesting that the reduction in DMBA-induced tumorigenicity is likely to be due, at least in part, to an increased rate of cell turnover in stromelysin-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 tumors compared to tumors from control mice. These results suggest that the expression of a single metalloproteinase, stromelysin-1, is insufficient for the progression of mammary adenocarcinomas to an invasive and metastatic phenotype, but that matrix degradation by metallproteinases can alter basic processes of cell proliferation and apoptosis.

¹ This work was supported by grants from the NIH (R01 CA46843 to L. M. M., R01 CA46413 to R. J. C., and a predoctoral fellowship to J. P. W., T32-CA09592). R. J. C. is a VA Clinical Investigator.

² To whom requests for reprints should be addressed, at Department of Cell Biology, MCN C-2310, Vanderbilt University, Nashville, TN 37232.

Received 12/30/94. Accepted 2/17/95.

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