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Published online on September 6, 2002, 10.1073/pnas.192172299
PNAS | September 17, 2002 | vol. 99 | no. 19 | 12263-12268


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

Immaculata De Vivo *, {dagger}, {ddagger} §, Gordon S. Huggins ¶, Susan E. Hankinson *, {dagger}, Pamela J. Lescault *, Marike Boezen ||, Graham A. Colditz *, {dagger}, {ddagger}, and David J. Hunter *, {dagger}, {ddagger}, ¶

*Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115; Departments of {dagger}Epidemiology and Nutrition, and {ddagger}Harvard Center for Cancer Prevention, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115; and ||Department of Epidemiology, University of Groningen, Ant. Deusinglaan 1, 9700 AD, Groningen, The Netherlands

Edited by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, and approved July 25, 2002 (received for review March 23, 2002)

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.

Abbreviations: hPR, human progesterone receptor; OR, odds ratio; BMI, body mass index; NHS, Nurses' Health Study; LD, linkage disequilibrium; SNP, single-nucleotide polymorphism; RACE, rapid amplification of cDNA ends; RT, reverse transcriptase

§ To whom reprint requests should be addressed. E-mail: devivo{at}channing.harvard.edu.

This paper was submitted directly (Track II) to the PNAS office.


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