A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk

Immaculata De Vivo, Gordon S. Huggins, Susan E. Hankinson, Pamela J. Lescault, Marike Boezen, Graham A. Colditz, David J. Hunter

Research output: Contribution to journalArticle

165 Scopus citations

Abstract

Excessive estrogen stimulation unopposed by progesterone strongly predisposes to endometrial cancer. Because the antiproliferative effect of progesterone requires the progesterone receptor (PR), which exists in two isoforms, PR-A and -B, we reasoned that variants in the PR gene may predispose to endometrial cancer. We found six variable sites, including four polymorphisms in the hPR gene and five common haplotypes. One promoter region polymorphism, +331G/A, creates a unique transcription start site. Biochemical assays showed that the +331G/A polymorphism increases transcription of the PR gene, favoring production of hPR-B in an endometrial cancer cell line. Using a case-control study nested within the Nurses' Health Study cohort, we observed a statistically significant association between the +331G/A polymorphism and the risk of endometrial cancer, which was even greater in overweight women carriers. After including a second population of controls, these associations remained intact. Our findings suggest that the +331G/A hPR gene polymorphism may contribute to endometrial cancer risk by increasing expression of the hPR-B isoform.

Original languageEnglish
Pages (from-to)12263-12268
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number19
DOIs
StatePublished - Sep 17 2002
Externally publishedYes

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