Overexpression of Aromatase Leads to Development of Testicular Leydig Cell Tumors

Abstract

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.

Aromatase ( Cyp19 ) expression is up-regulated by targeted disruption of Dax1

“…Acute treatment with estradiol has been shown to stimulate DNA synthesis and to cause LCH in murine Leydig cells (41). In addition, transgenic mice that overexpress aromatase exhibit LCH and an increased incidence of Leydig cell tumors (42). The finding that tamoxifen administration reduced the number of Leydig cells in the testes of Dax1-deficient mice is consistent with this mechanism of estrogen-induced LCH.…”

Functional significance of the rapid regulation of brain estrogen action: Where do the estrogens come from?

“…From a functional point of view, it would also probably be useful to produce estrogens locally where they are needed rather than flooding the entire organism with a compound that can have severe adverse effects (e.g. promote tumor growth, alter structure or function of reproductive organs, induce general toxicity, etc [5,27,94,99,134,154]) especially at the high doses that seem to be required to activate non-genomic responses (See below). Is it therefore possible that estrogens locally produced in the brain by aromatization of testosterone represent an endogenous stimulus triggering all or part of the fast non-genomic effects reviewed above.…”

Cytotoxicity of Synthetic Estrogen and Related Compounds in Various Tumor-Derived Cells.

“…[1][2][3][4][5][6][7][8][9] Among them, an involvement in carcinogenesis is of particular interest. [10][11][12] Consequently, the environmental effects of a synthetic estrogen, diethylstilbestrol (DES), large amounts of which have been used in stock-farming, have become a serious concern.We have shown that natural and synthetic estrogens and their related compounds have inhibitory activities on the in vitro polymerization of microtubule proteins, which play important roles in the cytoskeleton and cell division in addition to having hormonal activity. [13][14][15][16][17][18] We have also clarified that indenestrol A (IA), which is a metabolite of DES, has the highest antioxidant action among its related compounds.…”

“…[1][2][3][4][5][6][7][8][9] Among them, an involvement in carcinogenesis is of particular interest. [10][11][12] Consequently, the environmental effects of a synthetic estrogen, diethylstilbestrol (DES), large amounts of which have been used in stock-farming, have become a serious concern.…”