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A Germline Variation in the Progesterone Receptor Gene Increases Transcriptional Activity and May Modify Ovarian Cancer Risk

Departments of Molecular and Cellular Biology (I.U.A., N.L.W., D.G.K.) and Obstetrics and Gynecology (D.G.K.), Baylor College of Medicine, Houston, Texas 77030; Red Cross Blood Bank (K.K.), 89081 Ulm, Germany; Department of Biomathematics, University of Texas M. D. Anderson Cancer Center (N.E.A.), Houston, Texas 77030; Department of Pathology and Program in Molecular Biology, University of Colorado Health Sciences Center (D.P.E.), Denver, Colorado 80262; Department of Obstetrics and Gynecology, University Hospital Maastricht (D.-C.F., D.G.K.), 6202 AZ Maastricht, The Netherlands; Texas/United Kingdom Collaborative Research Initiative, Rice University (D.R.H.), Houston, Texas 77251; and Department of Obstetrics and Gynecology, Tongji University (X.-W.T.), 200065 Shanghai, People’s Republic of China

Address all correspondence and requests for reprints to: Dr. Dirk G. Kieback, Department of Obstetrics and Gynecology, Maastricht University Medical Center, P. Debyelaan 25, NL 6202 AZ Maastricht, The Netherlands. E-mail: dki{at}sgyn.azm.nl.

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.

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