Aromatase overexpression and breast hyperplasia, an in vivo model - continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands

To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonst rated for the first time that increased mammary estrogens resulting from th e overexpression of aromatase in mammary glands lead to the induction of va rious preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased brea st-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis , activation of genes involved in cell cycle and cell proliferation, and ac tivation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Pr eneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administrati on of the aromatase inhibitor, letrozole. Consistent with complete reductio n in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyp erplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is respo nsible for the induction of breast hyperplasia and these changes can be abr ogated using aromatase inhibitors.