Despite recent advances in diagnosis and treatment of testicular cancer, its causes remain unknown. The most common conditions known to be associated with testicular cancer are cryptorchidism, infertility, and overexposure to pesticides or radiation. Recent studies also indicate hormones may play a crucial role in testicular tumorigenesis. Our studies show that about half of the male transgenic mice overexpressing aromatase in testis were infertile and/or had larger than normal testicles. Gross pathology and histological analysis showed the mice to have Leydig cell tumors, unilaterally or bilaterally. Serum estradiol levels for transgenic mice were at least twice as high as those for nontransgenic mice. Expression of aromatase and estrogen receptor were also very high in testicular tissue of transgenic mice compared to nontransgenic mice. Consistent with increased estrogenic activity in the testicular tissue, we also saw an increase in the levels of genes involved in cell cycle that are regulated by the estrogen. To obtain a better understanding of the biological significance of testicular tumorigenesis, a reliable animal model is necessary to clarify the mechanisms and correlations associated with human cancers. Here we describe such a model, which shows that overexpression of aromatase results in increased estrogen production and a changed hormone milieu, leading to the induction of testicular cancer (Leydig cell tumors). This predictable and useful model is a potential tool for the study of testicular tumorigenesis, hormonal carcinogenesis, synergistic action of other carcinogens on hormone-induced tumors, and tumor dependency on endocrine factors.

To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-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 activation 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. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast Endocrine-Related Cancer (1999) 6 307-314 hyperplasia and these changes can be abrogated using aromatase inhibitors.

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