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Prolonged exposure to unopposed estrogens is a major risk factor for the development of endometrial cancer. Oxidative metabolism of estradiol (E2) into the catecholestrogens (CEs), 4-hydroxyestradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2), may play an important role in estrogen carcinogenicity. CEs can be oxidized to the corresponding ortho-quinone derivatives with concomitant formation of the reactive oxygen species (ROS). Catechol-O-methyltransferase (COMT) is the major enzyme involved in the detoxification of CEs in extrahepatic tissues. We investigated the potential of E2, 2-OHE2 and 4-OHE2 to induce microsatellite instability (MSI) and neoplastic transformation of immortalized human endometrial glandular (EM) cells. We also investigated the functional significance of COMT gene expression on modulating the effects of E2 and CEs in EM cells. Our data indicated that E2 and 4-OHE2 induce MSI, ROS and neoplastic transformation in EM cells. The capacity of E2 and its catechol metabolites to induce MSI, ROS and neoplastic transformation in EM cells is ranked as follows: 4-OHE2 > E2 > 2-OHE2. Knockdown of COMT expression in EM cells resulted in increased estrogenic milieu and increased estrogen-induced cell proliferation. More importantly, knockdown of COMT increased the propensity of E2 or CEs to induce ROS, MSI and neoplastic transformation of EM cells. In contrast, overexpression of COMT in EM cells significantly reduced the cellular estrogenic milieu and protected against E2- or CEs-induced, ROS, MSI and neoplastic transformation. The capacity of E2 or CEs to induce neoplastic transformation of human endometrial glandular cells in vitro may suggest that E2-induced endometrial cancer is mediated by its metabolism into CEs. Our study clearly indicates that COMT gene expression plays a critical role in modulating the hormonal and carcinogenic effects of E2 and CEs and, consequently, modifies the risk for E2-induced endometrial cancer. To the best of our knowledge, this is the first study to (i) demonstrate the potential capacity of estrogen and its catechol metabolites to induce neoplastic transformation of immortalized human endometrial glandular cells; and (ii) illustrate the important role of COMT gene expression in protecting against E2-induced endometrial cancer. © 2008 Wiley-Liss, Inc.