OVEREXPRESSION OF INT-5 AROMATASE IN MAMMARY-GLANDS OF TRANSGENIC MICE RESULTS IN THE INDUCTION OF HYPERPLASIA AND NUCLEAR ABNORMALITIES/

Our recent studies have shown that the cellular gene at the mouse mamm ary tumor virus integration site in the int-5 locus is aromatase. To s tudy the role of int-5/aromatase in normal mammary development and mam mary neoplasia, we have generated transgenic mice that overexpress int -5/aromatase under the control of mouse mammary tumor virus enhancer/p romoter. All the transgenic virgin (n = 10) and postlactational (n = 1 5) females that overexpress int-5/aromatase show various histological abnormalities, Overexpression of int-5/aromatase in mammary glands of virgin females leads to the enlargement of 40% of ducts, of which 65% had hyperplastic lesions, 20% had dysplastic lesions, and 15% had fibr oadenoma lesions, Overexpression of int-5/aromatase in involuted mamma ry glands of transgenic females induces hyperplasia in 75-80% of ducts and glands that exhibit a range of morphological abnormalities, inclu ding formation of hyperplastic alveolar nodule (10%), ductal and gland ular hyperplasia (70-80%), ductal and lobular dysplasia (15%), and nuc lear abnormalities (2-5%) such as multinucleation and karyomegaly, whi ch are all indicative of preneoplastic changes, Our results show that early exposure of mammary epithelium to in situ estrogen and continued exposure to in situ estrogen as a result of overexpression of int-5/a romatase appears to predispose mammary tissue to preneoplastic changes , which may, in turn, increase the risk of developing neoplasia and in crease susceptibility to environmental carcinogens, These findings sup port clinical and experimental data that suggest that early estrogen e xposure increases breast cancer risk.