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Association of the progesterone receptor gene with endometrial cancer risk in a Chinese population.

ABSTRACT: Single nucleotide polymorphisms (SNPs) in the progesterone receptor (PGR) gene have been associated with the risk of endometrial cancer. However, to the authors' knowledge, no study to date has systematically evaluated the role of the PGR gene in endometrial carcinogenesis.Exposure information and DNA samples collected in the Shanghai Endometrial Cancer Study, a population-based case-control study of 1,204 incident cases and 1,212 age- and frequency-matched population controls, were used in this study. Seven tag SNPs were identified for the PGR gene plus the 5-kilobase (kb) flanking regions using the Han Chinese data from the HapMap project with a pairwise correlation coefficient (r(2)) >or= 0.90. These 7 SNPs captured 92% of SNPs in the region with a pairwise r(2) >or= 0.90 or 100% of SNPs with a pairwise r(2) >or= 0.80. Genotyping of polymorphisms was performed by using the Affymetrix MegAllele Targeted Genotyping System. A logistic regression model was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs).Of 7 tag SNPs that were assessed, 2 polymorphisms in the 3' flanking region of the PGR gene, reference SNP identification number (rs) 11224561 (rs11224561) and rs471767, were associated with the risk of endometrial cancer. The cytosine/cytosine (CC) genotype of SNP rs11224561 was associated with decreased risk (OR, 0.68; 95% CI, 0.50-0.92) compared with the thymine/thymine (TT) genotype. Carrying the guanine (G) allele of the rs471767 SNP also was associated with decreased risk, although the association was not statistically significant (OR, 0.78, 95%CI, 0.59-1.04 and OR, 0.32, 95%CI, 0.03-3.05 for the adenine [A]G and GG genotypes, respectively, compared with the homozygote AA).The current findings suggested that polymorphisms in the 3' flanking region of the PGR gene may be associated with the risk of endometrial cancer.

SUBMITTER: Xu WH

PROVIDER: S-EPMC2746752 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Association of the progesterone receptor gene with endometrial cancer risk in a Chinese population.

Xu Wang-Hong WH Long Ji-Rong JR Zheng Wei W Ruan Zhi-Xian ZX Cai Qiuyin Q Cheng Jia-Rong JR Xiang Yong-Bing YB Shu Xiao-Ou XO

Cancer 20090601 12

<h4>Background</h4>Single nucleotide polymorphisms (SNPs) in the progesterone receptor (PGR) gene have been associated with the risk of endometrial cancer. However, to the authors' knowledge, no study to date has systematically evaluated the role of the PGR gene in endometrial carcinogenesis.<h4>Methods</h4>Exposure information and DNA samples collected in the Shanghai Endometrial Cancer Study, a population-based case-control study of 1,204 incident cases and 1,212 age- and frequency-matched pop ...[more]

PMID: 19382201

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Project description:Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term "molecularly enhanced progestin therapy." What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a previously unanticipated inverse relationship between the tumor suppressor PR and the oncogene Myc in endometrial cancer.

Dataset Information

Association of the progesterone receptor gene with endometrial cancer risk in a Chinese population.

Publications

Association of the progesterone receptor gene with endometrial cancer risk in a Chinese population.

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