Role of Estrogen Receptor Signaling Required for Endometriosis-Like Lesion Establishment in a Mouse Model

Abstract

Endometriosis results from ectopic invasion of endometrial tissue within the peritoneal cavity. Aberrant levels of the estrogen receptor (ER), ERα and ERβ, and higher incidence of autoimmune disorders are observed in women with endometriosis. An immunocompetent mouse model of endometriosis was used in which minced uterine tissue from a donor was dispersed into the peritoneal cavity of a recipient. Wild-type (WT), ERα-knockout (αERKO), and βERKO mice were donors or recipients to investigate the roles of ERα, ERβ, and estradiol-mediated signaling on endometriosis-like disease. Mice were treated with vehicle or estradiol, and resulting location, number, and size of endometriosis-like lesions were assessed. In comparison with WT lesions in WT hosts, αERKO lesions in WT hosts were smaller and fewer in number. The effect of ER status and estradiol treatment on nuclear receptor status, proliferation, organization, and inflammation within lesions were examined. αERKO lesions in WT hosts did not form distal to the incision site, respond to estradiol, or proliferate but did have increased inflammation. WT lesions in αERKO hosts did respond to estradiol, proliferate, and show decreased inflammation with treatment, but surprisingly, progesterone receptor expression and localization remained unchanged. Only minor differences were observed between WT lesions in βERKO hosts and βERKO lesions in WT hosts, demonstrating the estradiol-mediated signaling responses are predominately through ERα. In sum, these results suggest ER in both endometriosis-like lesions and their environment influence lesion characteristics, and understanding these interactions may play a critical role in elucidating this enigmatic disease.

Activated AKT Pathway Promotes Establishment of Endometriosis

“…The endometriotic 70-kDa SRC-1 C-terminal fragment prevented TNF␣-mediated apoptosis in human endometrial epithelial cells and caused epithelial-mesenchymal transition and the invasion of human endometrial cells. In another study, estrogen receptor-␣ (ER␣)-knockout and ER␤-knockout mice were used to study the role of ER and E2 in endometriosis (27). They induced endometriosis in these immunocompetent mice using the donor/recipient transplantation strategy and demonstrated the importance of ER␣ for establishment of endometriosis lesions.…”

Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis1

“…19) from those with WT endometria (11/17; 64.7%). One recipient of Klf13 null endometria displayed only non-adherent lesions (designated as 'floaters' in a previous study) [31] that were easily distinguished from adherent lesions due to their opaqueness and lack of vascularity. Another recipient of Klf13 null endometria also showed 'floaters' in addition to viable ectopic lesions.…”

“…Given the importance of ESR signaling in endometriosis pathology [31], we examined ESR isoform expression in ectopic lesions as a function of genotype. Klf13 null lesions had lower Esr1 but comparable Esr2 transcript levels (Fig.…”

“…3C). To confirm deregulation of ESR1 signaling with attenuated ESR1 expression as a function of lesion genotype, we evaluated the transcript levels of two known estrogen-responsive genes [31] by QPCR. Relative to those of WT lesions, lactoferrin (Ltf) and mucin 4 (Muc4) transcript levels were diminished in Klf13 null lesions (Fig.…”

The Relationship Among HOXA10, Estrogen Receptor α, Progesterone Receptor, and Progesterone Receptor B Proteins in Rectosigmoid Endometriosis: A Tissue Microarray Study

“…Those findings 25 and ours contradict previous findings that expression of ER-a is weak or absent in endometriosis, based on studies of ovarian and peritoneal lesions. 8,11,36 A possible explanation is that hormones and their receptors may have different actions in different cellular environments, 19,37 and this reinforces the possibility that pathogenesis in each of the 3 clinical forms of endometriosis is different.…”