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Department of Cell Biology, Vanderbilt University, Nashiville, Tennessee 37232 [L. A. R-O., L. M. M.]; and Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8S 4K1 [R. C., W. J. M.]
Overexpression of the epithelial specific matrix metalloproteinase matrilysin (MAT) has been correlated with enhanced tumorigenicity and tumor cell invasion using in vitro model systems. We have determined the effects of MAT expression on the development of mammary tumorigenesis using transgenic mice that express human MAT under the control of the mouse mammary tumor virus (MMTV)-long terminal repeat promoter/enhancer. Examination of mammary glands from multiparous MMTV-MAT animals revealed the development of premalignant hyperplastic alveolar nodules in 50% of aged females. MMTV-MAT mice were mated with MMTV-neu transgenic mice to determine the effect of MAT on neu-induced mammary tumorigenesis. Bigenic MMTV-MAT/neu female offspring developed primary mammary tumors 
13 weeks earlier than did MMTV-neu controls. The mechanism of enhanced neu-induced tumorigenesis was explored. No discernible difference in Neu receptor dimerization or activation was detected in MMTV-MAT/neu tumors or mammary glands compared to MMTV-neu controls. A similar percentage of MMTV-MAT/neu and MMTV-neu tumors acquired deletions in the neu transgene, which have previously been shown to result in constitutive receptor activation. The presence of premalignant nodules and the accelerated development of oncogene-induced mammary tumors suggest that expression of MAT in the mammary epithelium contributes to early-stage mammary tumorigenesis.
1 R. C. was supported by the Ontario Graduate Studentship and W. J. M. was a recipient of a Medical Research Council Scientist award. This work was partially supported by Canadian Breast Cancer Initiative Grant 6287-401 (to W. J. M.) and Department of Defense Grants DAMD 17-94-J-4226 (to L. M. M.) and Predoctoral Fellowship DAMD 17-94-J-4448 (to L. A. R-O.).
2 To whom requests for reprints should be addressed, at Department of Cell Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232. Phone: (615) 343-3413; Fax: (615) 343-4539; E-mail: lynn.matrisian@mcmail.vanderbilt.edu.
Received 5/11/98. Accepted 9/29/98.
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