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.
Highlights
Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and Single Nucleotide Polymorphisms (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
In our multiple linear regression models we found that having the minor homozygous allele was associated with decreased percent mammographic density for eight of our 34 SNPs: rs3020364 (p-value 0.01), rs2474148 (p-value 0.023), rs12154178 (p-value 0.026), rs2347867 (p-value 0.002), rs6927072 (p-value 0.007), rs2982712 p-value 0.006), rs3020407 (p-value 0.020), rs9322335 (p-value 0.024) (Table 2)
For all but two of these eight SNPs this association was seen in lean, but not in heavier women when we dichotomized our data by median split of body mass index (BMI) (Lean: ≤23.6, Heavy > 23.6)
Summary
Single 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. Mammographic density reflects the proportion of fibroglandular cells in the breast tissue; higher density indicates increased potential for proliferative activity [9] and is an established risk factor for breast cancer [10, 11]. Studies of associations between breast cancer risk factors and mammographic density has focused on percent mammographic density [12, 13], but on various mammographic density phenotypes [14,15,16,17] as absolute mammographic density is believed to represent the actual target tissue for tumor development [18,19,20,21]. Given the associations between estrogens and breast cancer, it is plausible that genetic variation in estrogen receptors may be important
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