The matrix metalloproteinase matrilysin influences early-stage mammary tumorigenesis

Overexpression of the epithelial specific matrix metalloproteinase matrilys in (MAT) has been correlated with enhanced tumorigenicity and tumor cell in vasion using in vitro model systems. We have determined the effects of MAT expression on the development of mammary tumorigenesis using transgenic mic e that express human MAT under the control of the mouse mammary tumor virus (MMTV)-long terminal repeat promoter/enhancer. Examination of mammary glan ds from multiparous MMTV-MAT animals revealed the development of premaligna nt hyperplastic alveolar nodules in 50% of aged females. MMTV-MAT mice were mated with MMTV-nea transgenic mice to determine the effect of MAT on neu- induced mammary tumorigenesis, Bigenic MMTV-MAT/neu female offspring develo ped primary mammary tumors similar to 13 weeks earlier than did MMTV-neu co ntrols. The mechanism of enhanced neu-induced tumorigenesis was explored. N o discernible difference in Neu receptor dimerization or activation was det ected in MMTV-MAT/neu tumors or mammary glands compared to MMTV-neu control s. A similar percentage of MMTV-MAT/neu and MMTV-neu tumors acquired deleti ons in the neu transgene, which have previously been shown to result in con stitutive receptor activation. The presence of premalignant nodules and the accelerated development of oncogene-induced mammary tumors suggest that ex pression of MAT in the mammary epithelium contributes to early-stage mammar y tumorigenesis.