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.
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.
Glace
Lindsay
L
Department of Urogenital Biology, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Grygielko
Eugene T
ET
Boyle
Ryan
R
Wang
Qi
Q
Laping
Nicholas J
NJ
Sulpizio
Anthony C
AC
Bray
Jeffrey D
JD
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
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