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(American Journal of Pathology. 2000;156:347-353.)
© 2000 American Society for Investigative Pathology

Animal Model

Overexpression of Aromatase Leads to Development of Testicular Leydig Cell Tumors

An in Vivo Model for Hormone-Mediated TesticularCancer

Keith A. Fowler{dagger}, Kiran Gill*, Nameer Kirma*, Dirck L. Dillehay{dagger} and Rajeshwar Rao Tekmal*

From the Department of Gynecology and Obstetrics*
and the Winship Cancer Center,{dagger}
Division of Animal Resources, Departments of Pathology and Laboratory Animal Medicine, Emory University School of Medicine, Atlanta, Georgia

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.




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