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Overexpression of int-5/aromatase in Mammary Glands of Transgenic Mice Results in the Induction of Hyperplasia and Nuclear Abnormalities¹

Department of Gynecology and Obstetrics and Winship Cancer Center [R. R. T., N. R., J. M.], Division of Animal Resources and Department of Pathology [D. L. D.], Emory University School of Medicine, Atlanta, Georgia 30322-4710; Department of Pathology, Baylor College of Medicine, Houston, Texas 77030 [S. G.]; Division of Clinical Immunology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78284 [V. R. D.]; and Department of Medical Chemistry, Kochi Medical School, Nankoku, Kochi 783, Japan [K. T., Y. S.]

Our recent studies have shown that the cellular gene at the mouse mammary tumor virus integration site in the int-5 locus is aromatase. To study the role of int-5/aromatase in normal mammary development and mammary neoplasia, we have generated transgenic mice that overexpress int-5/aromatase under the control of mouse mammary tumor virus enhancer/promoter. All the transgenic virgin (n = 10) and postlactational (n = 15) 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 fibroadenoma lesions. Overexpression of int-5/aromatase in involuted mammary glands of transgenic females induces hyperplasia in 75–80% of ducts and glands that exhibit a range of morphological abnormalities, including formation of hyperplastic alveolar nodule (10%), ductal and glandular hyperplasia (70–80%), ductal and lobular dysplasia (15%), and nuclear abnormalities (2–5%) such as multinucleation and karyomegaly, which 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/aromatase appears to predispose mammary tissue to preneoplastic changes, which may, in turn, increase the risk of developing neoplasia and increase susceptibility to environmental carcinogens. These findings support clinical and experimental data that suggest that early estrogen exposure increases breast cancer risk.

¹ This work was supported by NIH Grant CA57559 (to R. R. T.).

² To whom requests for reprints should be addressed, at Department of Gynecology and Obstetrics, Emory University School of Medicine, P. O. Box 21246, 1639 Pierce Drive, Atlanta, Georgia 30322-4710.

Received 3/ 8/96. Accepted 6/ 6/96.

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