title: Estrogen-induced stromal cell-derived factor-1 (SDF-1/Cxcl12) expression is repressed by progesterone and by Selective Estrogen Receptor Modulators via estrogen receptor alpha in rat uterine cells and tissues.
abstract: Endometriosis, defined as the presence of endometrial glands and stroma at extra-uterine sites, is a gynecological condition that affects women of reproductive age. Consistent with its uterine origins, endometriotic lesions and resulting symptoms are hormonally responsive. To investigate Progesterone Receptor (PR)-based therapies, we measured physiological endpoints and gene expression in rat models of uterine cell estrogenic activity. Estrogen-induced ELT-3 rat leiomyoma cell proliferation was significantly inhibited by progesterone (P4), while the antiprogestin RU486 or the Selective PR Modulator (SPRM) asoprisnil, did not block proliferation. Stromal cell-derived factor-1 (SDF-1/Cxcl12) gene expression was induced by estrogen, and was repressed by the Selective Estrogen Receptor Modulators (SERMs), the antiestrogen ICI 182,780, and P4, but not by RU486 or the ERbeta-selective ligand ERB-041. In ELT-3 cells, asoprisnil demonstrated partial PR agonism on SDF-1 gene repression. Magnetic Resonance Imaging was used to monitor development of ectopic cysts in a rat surgical model of endometriosis. SERMs and P4 significantly decreased cyst volumes comparably by approximately 60%. However, ERB-041 and asoprisnil had no effect on cyst volume, and RU486 increased cyst volume by 20%. SDF-1 expression was modestly, but significantly, increased in the cyst compared to eutopic uterus, and P4 and raloxifene could repress the expression. We showed that SDF-1 was similarly regulated in human cells. These data suggest that transcriptional regulation of SDF-1 is a surrogate marker of estrogenic activities via ERalpha in rat uterine cells, and that SDF-1 repression by PR agonists can predict the ability to oppose the actions of estrogen in vivo.
authors: Department of Urogenital Biology, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors: Lindsay
authors: L
authors: Glace
authors: Eugene T
authors: ET
authors: Grygielko
authors: Ryan
authors: R
authors: Boyle
authors: Qi
authors: Q
authors: Wang
authors: Nicholas J
authors: NJ
authors: Laping
authors: Anthony C
authors: AC
authors: Sulpizio
authors: Jeffrey D
authors: JD
authors: Bray
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003560:Cysts / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use*; D011372:Progestins / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; C478102:ERB 041; D004963:Estrenes; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006727:Hormone Antagonists; D010080:Oxazoles; D010091:Oximes; D011372:Progestins; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; D000077267:Fulvestrant; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; C488516:asoprisnil