A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk.
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.
De Vivo
Immaculata
I
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. devivo@channing.harvard.edu
Huggins
Gordon S
GS
Hankinson
Susan E
SE
Lescault
Pamela J
PJ
Boezen
Marike
M
Colditz
Graham A
GA
Hunter
David J
DJ
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics*; D012307:Risk Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014481:United States / Q000453:epidemiology
D020033:Protein Isoforms; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B