Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local aromatase expression. The question remains, then, what mediates estradiol action. Because estrogen receptor (ER)β levels in endometriosis are >100 times higher than those in endometrial tissue, this review focuses on this nuclear receptor. Deficient methylation of the ERβ promoter results in pathological overexpression of ERβ in endometriotic stromal cells. High levels of ERβ suppress ERα expression. A severely high ERβ-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor and increased cyclo-oxygenase-2 levels contributing to progesterone resistance and inflammation. ERβ-selective estradiol antagonists may serve as novel therapeutics of endometriosis in the future.

Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)β promoter resulting in pathologic overexpression of ERβ in endometriotic stromal cells. We speculate that alterations in the relative levels of ERβ and ERα in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERα--ERβ ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERβ and ERα leading to PR loss and progesterone resistance in endometriosis.

GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival.• GAS also showed resistance to radiotherapy.• GAS is therefore considered a distinct entity that should be distinguished from UEA. a b s t r a c tObjective. Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix. As shown in the original Japanese group description, in recent studies, GAS represents a more aggressive disease than the usual-type endocervical adenocarcinoma (UEA). Detailed clinicopathological features of this variant remain to be elucidated in a larger series of patients.Methods. Patients were enrolled by the Gynecologic Cancer Study Group of the Japan Clinical Oncology Group after receiving the approval of each Institutional Review Board. The study population comprised of women with stage I to II endocervical adenocarcinomas who underwent surgery between 2000 and 2009. Representative slides were evaluated by central pathological review (CPR), categorized into either GAS or UEA, and correlated with clinicopathological features and outcome.Results. Among the 393 enrolled patients with endocervical adenocarcinoma, 328 patients met the criteria for CPR and the study eligibility criteria and were included in further analysis. A total of 95 of the 328 tumors were classified as GAS. Compared with UEA, GAS was more significantly associated with bulky mass, deep stromal invasion, lymphovascular space invasion, parametrial invasion, ovarian metastasis, positive ascitic fluid cytology, j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y g y n o pelvic lymph node metastasis, and pathological (p) T stage but was not related to the degree of histological differentiation. Disease-free survival (P b 0.0001) and overall survival (P b 0.0001) were poorer in patients with GAS than in those with UEA.Conclusions. GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival. GAS is therefore considered a distinct entity that should be distinguished from UEA.Clinical trial information. UMIN Clinical Trials Registry: UMIN000007987

Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.

Estradiol (E2) stimulates the growth and inflammation in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Several clinical and laboratory-based observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptor (PR). In normal endometrium, progesterone acts via PR on stromal cells to induce secretion of paracrine factor(s) that in turn stimulate neighboring epithelial cells to express the enzyme 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2). HSD17B2 is an extremely efficient enzyme and rapidly metabolizes the biologically potent estrogen E2 to weakly estrogenic estrone. In endometriotic tissue, progesterone is incapable of inducing epithelial HSD17B2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate HSD17B2 may be due to the very low levels of PR observed in vivo in endometriotic tissue. The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this mitogen. The molecular details of this physiological paracrine interaction between the stroma and epithelium in normal endometrium and its lack thereof in endometriosis are discussed.

Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding noncancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%), and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis.

The antiphase expression of cry1 and Bmal1 may be preserved in ovarian cancers. The combination of cry1 and Bmal1 expression might become a possible prognostic marker in epithelial ovarian cancer.

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