Role of androgens in the growth of endometrial carcinoma: an in vivo animal model.

OBJECTIVE: We sought to create an animal model for the development of endometrial cancer in women with androgen excess. We examined the effects of estradiol and androgen, both alone and as precursors to estrogen biosynthesis on human endometrial cancers transplanted into a nude mouse model. STUDY DESIGN: We transplanted an estrogen-responsive, well-differentiated, established human endometrial carcinoma, EnCa-101, subcutaneously into athymic male nude mice. We established, first, that aromatase was expressed in this cell line, inducible by estrogen. We measured the growth of the tumor in the various groups weekly with Vernier calipers. We examined the effects of estradiol and androgens, both aromatizable and nonaromatizable, on tumor growth. RESULTS: Estrogen-supplemented tumors showed the greatest rate of growth and were significantly greater than the growth rate in castrate mice. Androgen-supplemented tumors showed a growth rate similar to that of tumors without significant hormonal exposure (castrate mice). Dihydrotestosterone had no effect on tumor growth in comparison with an agonadal state. CONCLUSIONS: Aromatizable and nonaromatizable androgens have little growth-promoting effect on a well-differentiated endometrial carcinoma. Estradiol is the most potent growth stimulus in our model.

Antiproliferative effect of interferon-gamma in human endometrial epithelial cells in vitro: potential local growth modulatory role in endometrium.

We previously reported that recombinant interferon-gamma (IFN-gamma) induces HLA-DR (human lymphocyte antigen) molecules of the major histocompatibility complex in human endometrial epithelial cells in vitro. We now report that IFN-gamma inhibits the proliferation of human endometrial epithelial cells and a human endometrial carcinoma cell line (EnCa101AE). Human endometrial epithelial cells expressed HLA-DR molecules and underwent morphological changes when exposed to IFN. Furthermore, the proliferation of these cells, as evidenced by nuclear labeling of bromodeoxyuridine (an analog of thymidine that is incorporated into cells in S phase), was markedly reduced, in a dose-dependent manner, by IFN-gamma. IFN-gamma induced HLA-DR expression, morphological changes, shedding from the substratum, and cell death in EnCa101AE cells. In addition, cell number and the numbers of bromodeoxyuridine-, Ki-67 (a nuclear marker of proliferation)-, and MPM-2 (a marker of mitotic cells)-positive cells were markedly lower in the EnCa101AE cultures treated with IFN-gamma than those in control cultures. The cytostatic and HLA-DR-inducing effects of IFN-gamma could be abrogated by neutralization with a polyclonal antibody, and IFN-gamma effects were reversible within days after its withdrawal. These findings indicate that IFN-gamma inhibits proliferation of human endometrial epithelial cells and suggest that this factor may locally regulate the proliferation of these epithelial cells in vivo.