Comparing regulation of the connexin43 gene by estrogen in uterine leiomyoma and pregnancy myometrium

Classical estrogen receptor (ER)-alpha is expressed in human myometrial and leiomyoma tissues from nonpregnant women. A comparison of these tissues shows that leiomyomas overexpress ER-alpha compared to normal myometrium. It was hypothesized that overexpression of ER-alpha in leiomyomas may account for observed overexpression of pregnancy-associated genes that are regulated by estrogen. For this reason, regulation of the labor-associated gene connexin43 (cx43) was compared in primary cultures of myometrial and leiomyoma cells. It was shown that a DNA element called activating protein (AP)-1 in the cx43 promoter is necessary for induction of cx43 gene transcription in primary uterine smooth muscle cells after activation of cellular protein kinases. However, estrogen did not induce myometrial cx43 gene transcription in vitro; instead, it inhibited AP-1 induction of cx43 expression. This is likely because the myometrial and leiomyoma cells begin to express the novel ER-beta upon culturing, and agonist-bound ER-beta is known to inhibit AP-1 activity. Interestingly, ER-beta is the predominant ER in myometrial tissue from pregnant women at term. Results from an examination of pregnancy myometrial tissue support the concept that AP-1 activity is involved in the induction of myometrial cx43 expression at term and that suppression of ER-beta expression is needed for this induction. As pregnancy myometrium expresses primarily ER-beta, and nonpregnancy leiomyomas express primarily ER-alpha, AP-1 activity is predicted to be suppressed in pregnancy myometrium and elevated in leiomyomas under the influence of estrogen. This may be important in understanding tumor pathology, as AP-1 activity is associated with cell growth.