Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.

Abstract

BackgroundSingle nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown.MethodsWe assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol.ResultsWe observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002–0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3–6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025–0.079) that the level of 17β-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype.ConclusionOur results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2804-1) contains supplementary material, which is available to authorized users.

Field cancerization in breast cancer

“…Similarly, exogenous hormone use also influences breast density [36]. Studies correlating endogenous hormone levels and breast density are inconsistent [37,38], probably due to multiple confounding factors, though a relationship is supported by the association between some SNPs in the ESR1 gene and percent mammographic density [39]. Similarly, in both pre-and post-menopausal women, higher circulating levels of estrogen metabolites are associated with significantly higher TDLU counts and reduced lobular involution [40].…”

The rs9340799 polymorphism of the estrogen receptor alpha (ESR1) gene and its association with breast cancer susceptibility

“…For this reason, many genetic association studies have investigated the relationship between ESR1 polymorphisms and BC susceptibility. These polymorphisms include, but not limited to, rs9340799, rs3020364, rs9322335, rs2234693, rs1801132, rs2046210, rs3020314, rs1514348, rs3020314, rs1514348, rs1514348 and rs3020314 35 , 60 – 63 .…”

Effect of ovariectomy on maxilla and mandible dimensions of female rats

“…We hypothesize that other mechanisms could be involved in the variation of this expression, such as epigenetic factors and microRNAs, 45,46 or genetic polymorphisms in the encoding genes ESR1 and ESR2 . These polymorphisms could be involved in the variations of the receptor transcription, 47 what could affect the maxilla and mandible growth and development 48 . Although oestrogen levels do not regulate the expression of its receptors, it is important to emphasize that oestrogen‐regulated pathways involved in growth processes are mediated by direct interaction of this molecule with ERα and ERβ 49 .…”