title: A germline variation in the progesterone receptor gene increases transcriptional activity and may modify ovarian cancer risk.
abstract: Recently, we and others have detected a haplotype of the human progesterone receptor gene (PR). This haplotype consists of a 320-bp insertion in intron G together with point mutations in exons 4 and 5 and was named PROGINS. Whereas the exon 5 mutation is silent, the mutation in exon 4 results in a V660L substitution. Interestingly, this genetic polymorphism was seen to cosegregate with an increased risk of sporadic ovarian cancer in different ethnic groups. Our data provide evidence for the existence of an epidemiological link between a mutated progesterone receptor allele and ovarian cancer (odds ratio, 3.02; 95% confidence interval, 1.86-4.91). Functional characterization of the mutated receptor protein revealed a greater transcriptional activity compared with the wild-type receptor. By contrast, hormone binding and hormone dissociation rates were similar in both receptor proteins. We found that the increased transcriptional activity was due to increased stability resulting in higher expression of the mutant protein. Thus, the long-lasting hyperactivation of progesterone receptor-driven genes secondary to the increased transcriptional activity of the mutated progesterone receptor may participate in ovarian carcinogenesis. This is of special interest, because only a few genetic markers are available for the majority of women diagnosed with sporadic ovarian cancer.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Irina U
authors.initials: IU
authors.lastname: Agoulnik
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Tong
authors.forename: Dagmar-C
authors.initials: DC
authors.lastname: Fischer
authors.forename: Klaus
authors.initials: K
authors.lastname: Körner
authors.forename: Neely E
authors.initials: NE
authors.lastname: Atkinson
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
authors.forename: Denis R
authors.initials: DR
authors.lastname: Headon
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Kieback
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D004251:DNA Transposable Elements; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007438:Introns; D009994:Osmolar Concentration; D010051:Ovarian Neoplasms / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D004251:DNA Transposable Elements; D006728:Hormones; D011980:Receptors, Progesterone