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Departments of¹ Medical Technology² Obstetrics and Gynecology³ Pathology, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan⁴ Research Institute for Clinical Oncology⁵ Division of Breast Surgery, Saitama Cancer Center, Saitama 362-0806, Japan

(Correspondence should be addressed to M Matsumoto, Department of Obstetrics and Gynecology, Tohoku University School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; Email: m-matsumoto{at}mail.tains.tohoku.ac.jp)

The estrogen pathway plays an important role in the etiology of human endometrial carcinoma (EC). We examined whether estrogen biosynthesis in the tumor microenvironment promotes endometrial cancer. To examine the contribution of stromal cells to estrogen signaling in EC, we used reporter cells stably transfected with the estrogen response element (ERE) fused to the destabilized green fluorescent protein (GFP) gene. In this system, the endometrial cancer stromal cells from several patients activated the ERE of cancer cells to a variable extent. The GFP expression level increased when testosterone, a substrate for aromatase, was added. The effect was variably inhibited by aromatase inhibitors (AIs), although the response to AIs varied among patients. These results suggest that GFP expression is driven by estrogen synthesized by aromatase in the endometrial cancer stromal cells. In a second experiment, we constructed an adenovirus reporter vector containing the same construct as the reporter cells described above, and visualized endogenous ERE activity in primary culture cancer cells from 15 EC specimens. The GFP expression levels varied among the cases, and in most primary tissues, ERE activities were strongly inhibited by a pure anti-estrogen, fulvestrant. Interestingly, a minority of primary tissues in endometrial cancer showed ERE activity independent of the estrogen-ER pathway. These results suggest that AI may have some therapeutic value in EC; however, the hormonal microenvironment must be assessed prior to initiating therapy.

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				N. Takahashi-Shiga, H. Utsunomiya, Y. Miki, S. Nagase, R. Kobayashi, M. Matsumoto, H. Niikura, K. Ito, and N. Yaegashi Local Biosynthesis of Estrogen in Human Endometrial Carcinoma through Tumor-Stromal Cell Interactions Clin. Cancer Res., October 1, 2009; 15(19): 6028 - 6034. [Abstract] [Full Text] [PDF]