Uterine leiomyomas express myometrial contractile-associated proteins involved in pregnancy-related hormone signaling

Abstract

We used an animal model to study uterine leiomyoma in the context of pregnancy-associated changes in gene expression and to determine how they might modulate tumor growth. Spontaneous tumors and normal myometrium were collected from Eker rats and compared with myometrial samples from pregnant animals. A leiomyoma-derived cell line was also used to assess pregnancy-related changes in gene expression and to determine the impact of signaling by the oxytocin receptor. Eker rat leiomyomas expressed several pregnancy-related genes, including connexin 43, oxytocin receptor (OTR), and cyclooxygenase (COX)-1; however, the tumors did not express COX-2, which is expressed in the parturient myometrium. The leiomyoma-derived cell lines also expressed OTR, which responds to estrogen, binds to oxytocin, and exhibits a calcium flux when stimulated with oxytocin. The OTR signaling mediated by oxytocin inhibited estrogen-stimulated growth of leiomyoma cells. Leiomyoma cells expressed many genes of the parturient myometrium, including OTRs, but were deficient in COX-2 expression. Signaling via the OTR appears to inhibit estrogen-induced cell proliferation, suggesting that signaling by this receptor might help mediate the protective effect of pregnancy on this disease.

Uterine myomas during pregnancy: a longitudinal sonographic study

“…Increase in myoma size during the first half of pregnancy was influenced negatively by parity and positively by prepregnancy BMI, while only maternal age correlated negatively with myoma growth over the entire course of pregnancy. With respect to parity, it is possible that the repeated puerperal remodeling process responsible for the involution of myomas denies these neoplasms of their source of nutrition, thereby preventing their growth in a subsequent pregnancy17. The role of prepregnancy BMI in the volumetric increase of myomas in the first period of pregnancy can probably be ascribed to the increased conversion of circulating adrenal androgens to estrone by fat tissue and to the decreased hepatic synthesis of sex hormone‐binding globulin (SHBG) at the beginning of pregnancy due to an increase of active estrogens18.…”

Surgical Management of Uterine Fibroids at Aminu Kano Teaching Hospital

“…Paradoxically, fibroids will rarely grow during pregnancy despite very high steroid hormone levels, and pregnancy appears to exact a protective effect. The mechanism(s) by which pregnancy exerts its protective effects is unclear, but may be mediated by an interaction of estrogen, prostaglandins, and oxytocin [18, 19]. This is said to explain why the incidence of uterine fibroids is decreased with increasing number of term pregnancies [18], although studies from Nigeria [5] did not agree with this.…”

MAPK14 Cooperates with MAPK3/1 to Regulate Endothelin-1-Mediated Prostaglandin Synthase 2 Induction and Survival in Leiomyoma but Not in Normal Myometrial Cells1

“…These data confirm that MAPK14 and MAPK3/1 were not sequentially activated, and that no direct crosstalk occurred between MAPK3/1 and MAPK14 signaling pathways activated by ET-1 or S6c. In ELT3 cells, it has been shown that PTGS2 (COX2) expression and subsequent PGE2 production are up-regulated [31]. PTGS2 expression is regulated by different MAPK [26,27].…”

“…), which play an important role in uterine physiology and pathology [14,29]. It has been demonstrated that, in primary leiomyoma tumors and leiomyoma-derived ELT3 cells, PTGS2 expression and subsequent PGE2 production are up-regulated [31]. Furthermore, PTGS2 expression plays a crucial role in leiomyoma growth in an in vivo model [32].…”