Adenovirus-mediated delivery of a dominant-negative estrogen receptor gene in uterine leiomyoma cells abrogates estrogen- and progesterone-regulated gene expression

Context: Human uterine leiomyomas are very common smooth muscle cell tumors that occur in reproductive- age women and are the leading reason for performing hysterectomies. The present study was conducted to explore the potential mechanism behind the effects exerted by dominant- negative estrogen receptors ( DNERs) delivered by adenovirus to leiomyoma cells to ascertain the utility of DNERs as a novel strategy for treatment of uterine fibroids. Objective and Methods: We investigated the ability of DNER to affect estrogen response element ( ERE) activity induced by wild- type estrogen receptor ( ER) by using the adenovirus ERE luciferase ( Ad-ERE- luc) system in ELT3 cells and the effect of graded doses of DNER ( 10, 50, and 100 plaque- forming units/ cell) on the expression of some selected genes controlling cultured human leiomyoma cell proliferation ( cyclin D1, Cox2, PCNA, VEGF, and EGF), apoptosis ( Bcl2 and Bax), estrogen metabolism ( COMT), and extracellular matrix formation (MMP1) as well as progesterone receptors ( A and B) were assessed using Western blot analysis. These genes are all regulated by estrogen and/ or progesterone. Results: DNER has the ability to suppress the ERE luc activity induced by wild- type ER ( P < 0.01) and significantly ( P < 0.05) reverse the expression of all estrogen- and progesterone- regulated genes in this study. Conclusions: These results suggest that interruption of the estrogen signaling pathway using DNER results in modulation of both estrogen- and progesterone- regulated genes that control leiomyoma cell apoptosis, proliferation, extracellular matrix formation, progesterone receptors, and estrogen metabolism, which might account for the DNER mechanism of action.