Progesterone Receptor Gene Polymorphisms and Breast Cancer Risk

Abstract

The objective of this systematic review was to investigate the association between polymorphisms in the progesterone receptor gene (PGR) and breast cancer risk. A search of PubMed, Scopus, and Web of Science databases was performed in November 2021. Study characteristics, minor allele frequencies, genotype frequencies, and odds ratios were extracted. Forty studies met the eligibility criteria and included 75 032 cases and 89 425 controls. Of the 84 PGR polymorphisms reported, 7 variants were associated with breast cancer risk in at least 1 study. These polymorphisms included an Alu insertion (intron 7) and rs1042838 (Val660Leu), also known as PROGINS. Other variants found to be associated with breast cancer risk included rs3740753 (Ser344Thr), rs10895068 (+331G/A), rs590688 (intron 2), rs1824128 (intron 3), and rs10895054 (intron 6). Increased risk of breast cancer was associated with rs1042838 (Val660Leu) in 2 studies, rs1824128 (intron 3) in 1 study, and rs10895054 (intron 6) in 1 study. The variant rs3740753 (Ser344Thr) was associated with decreased risk of breast cancer in 1 study. Mixed results were reported for rs590688 (intron 2), rs10895068 (+331G/A), and the Alu insertion. In a pooled analysis, the Alu insertion, rs1042838 (Val660Leu), rs3740753 (Ser344Thr), and rs10895068 (+331G/A) were not associated with breast cancer risk. Factors reported to contribute to differences in breast cancer risk associated with PGR polymorphisms included age, ethnicity, obesity, and postmenopausal hormone therapy use. PGR polymorphisms may have a small contribution to breast cancer risk in certain populations, but this is not conclusive with studies finding no association in larger, mixed populations.

Keywords: +331G/A; Alu insertion; PROGINS haplotype; breast cancer; progesterone receptor; single nucleotide polymorphism.

Figure 1.

Flow diagram demonstrating the study selection process for this systematic review.

Figure 2.

Polymorphism locations in the human progesterone receptor gene (PGR) reported to be associated with breast cancer risk. PGR is located on chromosome 11 and is comprised of 8 exons and 7 introns. The PGR gene maps to 101,019,603-101,139,830 in GRCh38.p13 coordinates. Exon coordinates and polymorphism locations can be found on the NCBI Variation Viewer website (https://www.ncbi.nlm.nih.gov/variation/view/). Polymorphisms reported to have an association with breast cancer in at least 1 study have been found in the 5′ untranslated region, within exons and introns. These polymorphisms include rs10895068 (+331G/A), rs3740753 (Ser344Thr), rs590688 (intron 2), rs1824128 (intron 3), rs1042838 (Val660Leu), rs10895054 (intron 6), and the Alu insertion (intron 7). The PROGINS haplotype consists of the Alu insertion (intron 7), rs1042838 (Val660Leu), and rs1042839 (His770His). Polymorphisms with no association with breast cancer risk are detailed in Table 2 and elsewhere (Table S1 (94)). Separate promoters are utilized to encode for 2 predominant progesterone receptor (PR) protein isoforms, PR-B (933 amino acids) and PR-A (769 amino acids; lacks first 164 amino acids in the N-terminus). NTD, N-terminal domain; DBD, DNA binding domain; H , hinge; LBD, ligand binding domain.

Figure 3.

Forest plot of association between Alu insertion and breast cancer risk. Data for Caucasian and African American women were combined for Donaldson et al (44). Data for Runnebaum et al (70) were calculated from percentages reported. Cases, individuals with breast cancer. Controls, individuals without breast cancer. Yes, heterozygote + rare homozygote. No, major allele homozygote. OR, odds ratio (unadjusted).

Figure 4.

Forest plot of association between rs1042838 (Val660Leu) and breast cancer risk. Data for European American and African American women were combined for Gabriel et al (48). Cases, individuals with breast cancer. Controls, individuals without breast cancer. Yes, heterozygote + rare homozygote. No, major allele homozygote. OR, odds ratio (unadjusted).

Figure 5.

Forest plot of association between PROGINS and breast cancer risk. Red, Alu insertion. Black, rs1042839 (His770His). Blue, rs1042838 (Val660Leu). Note that the study by Fabjani et al (45) included both rs1042838 (Val660Leu) and rs1042839 (His770His). Data for European American and African American women were combined for Gabriel et al (48) Cases, individuals with breast cancer. Controls, individuals without breast cancer. Yes, heterozygote + rare homozygote. No, major allele homozygote. OR, odds ratio (unadjusted).

Figure 6.

Forest plot of association between rs3740753 (Ser344Thr) and breast cancer risk. Cases, individuals with breast cancer. Controls, individuals without breast cancer. Yes, heterozygote + rare homozygote. No, major allele homozygote. OR, odds ratio (unadjusted).

Figure 7.

Forest plot of association between rs10895068 (+331G/A) and breast cancer risk. Cases, individuals with breast cancer. Controls, individuals without breast cancer. Yes, heterozygote + rare homozygote. No, major allele homozygote. OR, odds ratio (unadjusted).