Differential association of ESR1 and ESR2 gene variants with the risk of breast cancer and associated features: A case-control study

Abstract

Background: Estrogen is key to breast cancer pathogenesis, and acts by binding its receptor (ER), which exists as ERα and ERβ, encoded by ESR1 and ESR2 genes, respectively. Studies that investigated the association of ESR1 and ESR2 variants with breast cancer yielded mixed outcome, and ethnic contribution was proposed. We evaluated the association between ESR1 and ESR2 variants and breast cancer and associated features in Tunisian women.

Methods: Retrospective case-control study involving 207 female breast cancer patients, and 284 control women. Genotyping was done by real-time PCR.

Results: Minor allele frequencies (MAF) of tagging SNPs rs2234693 and rs3798577 (ESR1) were significantly higher, while MAF of rs1256049 (ESR2) was significantly lower in breast cancer patients vs.

Controls: Patients carrying rs3798577 genotypes had higher risk, while rs1256049 genotype carriers had reduced risk of breast cancer. The association of ESR1 and ESR2 gene variants with breast cancer depended on ER and Her-2 status. ESR1 rs3798577 and ESR2 rs1256049 were associated with breast cancer in ER-positive cases, and ESR1 rs2234693, and rs3798577 were associated with breast cancer in Her-2-negative cases, while the association of ESR2 rs1256049 with breast cancer was seen in Her-2 positive cases. Haploview analysis identified 4-locus ESR1 haplotypes that were positively (CGTT, TACC, and TACT), and negatively (CGTC) associated with breast cancer. No ESR2 haplotypes associated with breast cancer were identified.

Conclusion: ESR1 alleles and genotypes, and specific 3-locus ESR1 haplotypes are related with increased breast cancer susceptibility in Tunisian women. However, ESR2 variant and specific 1-locus ESR1 haplotype have a protective effect.

Keywords: Breast cancer; Estrogen; Estrogen receptor; Genotypes; Haplotypes.