title: Functionality of the progesterone receptor in ovarian cancer and its regulation by estrogen.
abstract: Here, we sought to obtain evidence that the progesterone receptor (PR) may be functional in ovarian cancer and regulated by estrogen. Megestrol acetate inhibited growth of the PR-positive PE04 ovarian carcinoma xenograft but not the PR-negative HOX 60 xenograft. PR concentration was higher in early-stage (I/II) tumors than in advanced-stage (III/IV) tumors (P = 0.007) and in tumors of endometrioid histology compared to other carcinoma subtypes (P = 0.009). Patients with a tumor PR concentration of >40 fmol/mg protein had significantly improved survival over those patients whose tumors contained <40 fmol/mg (P = 0.0007; log-rank). Evidence of PR regulation by estrogen was obtained by endocrine manipulation of the PE04 xenograft. PR content of PE04 xenografts fell from 145 to 7 fmol/mg protein in ovariectomized mice and was 2 fmol/mg in male mice. Administration of 17-beta-estradiol increased PR content to 745 fmol/mg. In primary ovarian carcinomas, PR was significantly associated with ER concentrations (P < 0.0001), suggesting regulation of PR levels by estrogen. This association was present for tumors of endometrioid histology (P < 0.0001) but not for those with serous histology (P = 0.31). These data point to the regulation of PR levels by estrogen in ovarian cancer and to a mediatory role for PR in the inhibition of growth induced by progestin.
authors.affiliation: Imperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, Edinburgh, United Kingdom. s.langdon@icrf.icnet.uk
authors.forename: S P
authors.initials: SP
authors.lastname: Langdon
authors.forename: H
authors.initials: H
authors.lastname: Gabra
authors.forename: J M
authors.initials: JM
authors.lastname: Bartlett
authors.forename: G J
authors.initials: GJ
authors.lastname: Rabiaz
authors.forename: R A
authors.initials: RA
authors.lastname: Hawkins
authors.forename: A L
authors.initials: AL
authors.lastname: Tesdale
authors.forename: A A
authors.initials: AA
authors.lastname: Ritchie
authors.forename: W R
authors.initials: WR
authors.lastname: Miller
authors.forename: J F
authors.initials: JF
authors.lastname: Smyth
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D019290:Megestrol Acetate / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000648:ultrastructure*; D011960:Receptors, Estrogen / Q000502:physiology; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol; D019290:Megestrol Acetate