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.