Stromal PRs Mediate Induction of 17β-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Endometrial Epithelium: A Paracrine Mechanism for Inactivation Of E2

Abstract

Progesterone stimulates the expression of 17beta-hydroxysteroid dehydrogenase (HSD) type 2, which catalyzes the conversion of the potent estrogen, E2, to an inactive form, estrone, in epithelial cells of human endometrial tissue. Various effects of progesterone on uterine epithelium have recently been shown to be mediated by stromal PRs in mice. We describe herein a critical paracrine mechanism whereby progesterone induction of 17beta-HSD type 2 enzyme activity, transcript levels, and promoter activity in human endometrial epithelial cells are mediated primarily by PR in endometrial stromal cells. Medium conditioned with progestin-pretreated human endometrial stromal cells robustly increased 17beta-HSD type 2 enzyme activity (2-fold) and mRNA levels (13.2-fold) in Ishikawa malignant endometrial epithelial cells. In contrast, direct progestin treatment of Ishikawa epithelial cells gave rise to much smaller increases in enzyme activity (1.2-fold) and mRNA levels (4-fold). These results suggest that progesterone- dependent paracrine factors arising from stromal cells are primarily responsible for the induction of epithelial 17beta-HSD type 2 expression in the endometrium. We transfected serial deletion mutants of the -1,244 bp 5'-flanking region of the 17beta-HSD type 2 gene into Ishikawa cells. No progesterone response elements could be identified upstream of the 17beta-HSD type 2 promoter. Stromal PR-dependent induction of the 17beta-HSD type 2 promoter was mediated by a critical regulatory region mapped to the -200/-100 bp sequence. Direct treatment of Ishikawa cells with progestin gave rise to a maximal increase in the activity of -200 bp/Luciferase construct only by 1.2-fold, whereas medium conditioned by progestin-pretreated endometrial stromal cells increased promoter activity up to 2.4-fold in a time- and concentration-dependent manner. The stimulatory effect of medium conditioned by progestin-pretreated stromal cells was enhanced strikingly by increasing stromal cell PR levels with the addition of estrogen. This epithelial-stromal interaction was specific for endometrial epithelial cells, since 17beta-HSD type 2 could not be induced in malignant breast epithelial cells by media conditioned with progestin-treated breast or endometrial stromal cells. In conclusion, progesterone regulates the conversion of biologically active E2 to estrone by inducing the 17beta-HSD type 2 enzyme in human endometrial epithelium primarily via PR in stromal cells, which secrete factors that induce transcription mediated primarily by the -200/-100 bp 5'-regulatory region of the 17beta-HSD type 2 promoter.

Ratio of 17HSD1 to 17HSD2 Protein Expression Predicts the Outcome of Tamoxifen Treatment in Postmenopausal Breast Cancer Patients

“…We found that the expression of 17HSD1 and 17HSD2 was significantly correlated, which indicates that the enzymes are coregulated. It is known that progesterone and progestins influence 17HSD1 and 17HSD2 expression in breast cancer cells and endometrial cells (19,20). However, in this study, such influences are less likely because the patients were postmenopausal.…”

“…No associations were found with 17HSD2 and survival. In premenopausal women, 17HSD2 is regulated by progesterone during the menstrual cycle, and because it was not known on which day of the cycle the patients were operated on, it is difficult to draw conclusions based on 17HSD2 in this group (20,25).…”

Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

“…We also demonstrated that 17-HSD type 2 was only detected in the cytoplasm of the glandular cells during the secretory phase, but not in the proliferative phase endometrium [19,34]. In addition, progestin stimulates the expression of 17-HSD type 2 in epithelial cells of human endometrial tissue [60]. Progestin may exert a potent anti-estrogenic effect in the endometrium by inducing 17-HSD type 2 and thereby promoting the regression of endometrial proliferative disease.…”

Progestin therapy for endometrial cancer: The potential of fourth-generation progestin (Review)

“…17-HSD type 2 is detected in the glandular cell cytoplasm only during the endometrial secretory phase and is not detected during the proliferative phase. In endometrial tissue epithelial cells, progestin stimulates the expression of 17-HSD type 2 (15). Progestin in endometrial tissue has the possibility of exerting anti-estrogen activity in the endometrium through inducing 17-HSD type 2 and stimulating the remission of endometrial hyperplastic disease.…”