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A germline variation in the progesterone receptor gene increases transcriptional activity and may modify ovarian cancer risk.

A germline variation in the progesterone receptor gene increases transcriptional activity and may modify ovarian cancer risk.

Authors :
Agoulnik IU
Tong XW
Fischer DC
Körner K
Atkinson NE
Edwards DP
Headon DR
Weigel NL
Kieback DG
Source :
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2004 Dec; Vol. 89 (12), pp. 6340-7.
Publication Year :
2004

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.

Details

Language :
English
ISSN :
0021-972X
Volume :
89
Issue :
12
Database :
MEDLINE
Journal :
The Journal of clinical endocrinology and metabolism
Publication Type :
Academic Journal
Accession number :
15579801
Full Text :
https://doi.org/10.1210/jc.2004-0114