The Matrix Metalloproteinase Matrilysin Influences Early-Stage Mammary Tumorigenesis1

Overexpression of the epithelial specific matrix metalloproteinase inatrilysin (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 MMTVUt / animals revealed the development of premalignant hyperplastic alveolar nodules in 50% of aged females. M\lT\-.\7. t'/' mice were mated with MMTV-neu transgenic mice to determine the effect of MAT on niu-induced mammary tumorigenesis. Bigenic MMTV-AM Tine u female offspring developed primary mammary tumors -13 weeks earlier than did MM I \ -»i »controls. The mechanism of enhanced neu-induced tu morigenesis was explored. No discernible difference in Neu receptor dimeri/.ution or activation was detected in MM l\ -.U.I//»<•» tumors or mammary glands compared to MMT\ -»<•» controls. A similar percentage of MMTV-M/4 T/neu and MMTV-neu tumors acquired deletions in the ¡»•it transgene, which have previously been shown to result in constitutive receptor activation. The presence of premalignant nodules and the accel erated development of oncogene-induced mammary tumors suggest that expression of MAT in the mammary epithelium contributes to early-stage mammary tumorigenesis.