Catecholestrogens induce oxidative stress and malignant transformation in human endometrial glandular cells: Protective effect of catechol‐O‐methyltransferase

Abstract

Prolonged exposure to unopposed estrogens is a major risk factor for the development of endometrial cancer. Oxidative metabolism of estradiol (E 2 ) into the catecholestrogens (CEs), 4-hydroxyestradiol (4-OHE 2 ) and 2-hydroxyestradiol (2-OHE 2 ), 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 E 2 , 2-OHE 2 and 4-OHE 2 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 E 2 and CEs in EM cells. Our data indicated that E 2 and 4-OHE 2 induce MSI, ROS and neoplastic transformation in EM cells. The capacity of E 2 and its catechol metabolites to induce MSI, ROS and neoplastic transformation in EM cells is ranked as follows: 4-OHE 2 > E 2 > 2-OHE 2 . 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 E 2 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 E 2 -or CEs-induced, ROS, MSI and neoplastic transformation. The capacity of E 2 or CEs to induce neoplastic transformation of human endometrial glandular cells in vitro may suggest that E 2 -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 E 2 and CEs and, consequently, modifies the risk for E 2 -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 E 2 -induced endometrial cancer. ' 2008 Wiley-Liss, Inc. Key words: catecholestrogens;COMT; genomic instability; endometrial cancer Endometrial cancer is the most common cancer of the genital tract in American women and ranks first in incidence and second in mortality among gynecological malignancies. 1 It is estimated that the rates of endometrial cancer in American women are among the highest in the world. 2 The risk factors for endometrial cancer include nulliparity, early age at menarche, late age at menopause, obesity and long-term use of estrogen replacement therapy (ERT). These risk factors seem to relate, either directly or indirectly, prolonged exposure to an unopposed estrogen. 3 Most endometrial carcinomas are Type I estrogen-associated endo...

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Are estradiol metabolites involved in gynaecological carcinogenesis?

“…Animal experiments showed a mutagenic effect of 4-hydroxyestradiolquinones (33,34). Of further interest are the results of Salama et al (35), who demonstrated that catechol oestrogens induce oxidative stress in human endometrial cells and trigger malignant transformation that was inhibited by addition of catechol-O-methyltransferase.…”