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

F N Fjeldheim; H Frydenberg; V G Flote; A McTiernan; A-S Furberg; P T Ellison; E S Barrett; T Wilsgaard; G Jasienska; G Ursin; E A Wist; I Thune

doi:10.1186/s12885-016-2804-1

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

BMC Cancer. 2016 Oct 7;16(1):776. doi: 10.1186/s12885-016-2804-1.

Authors

F N Fjeldheim^{1

2}, H Frydenberg³, V G Flote³, A McTiernan⁴, A-S Furberg^{5

6}, P T Ellison⁷, E S Barrett⁸, T Wilsgaard⁵, G Jasienska⁹, G Ursin¹⁰, E A Wist^{3

11}, I Thune^{3

12}

Affiliations

¹ The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway. frnfje@ous-hf.no.
² Institute of Clinical Medicine, University of Oslo, Oslo, N-0316, Norway. frnfje@ous-hf.no.
³ The Cancer Centre, Oslo University Hospital, Oslo, N-0424, Norway.
⁴ Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA, USA.
⁵ Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
⁶ Department of Microbiology and Infection Control, University Hospital of North Norway, 9038, Tromsø, Norway.
⁷ Department of Anthropology, Harvard University, 11 Divinity Avenue, Cambridge, MA, 02138, USA.
⁸ Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
⁹ Department of Environmental Health, Institute of Public Health, Jagiellonian University Medical College, Grzegorzecka 20, Krakow, 31-351, Poland.
¹⁰ Cancer Registry of Norway, PO Box 5313, Majorstuen, Oslo, N-0304, Norway.
¹¹ Institute of Clinical Medicine, University of Oslo, Oslo, N-0316, Norway.
¹² Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037, Tromsø, Norway.

Abstract

Background: 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. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown.

Methods: We 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.

Results: We 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/m^2.). 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.

Conclusion: Our 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.

Keywords: 17β-estradiol; ESR1; Mammographic density; Polymorphisms; Premenopausal.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Breast Density*
Estradiol / blood
Estrogen Receptor alpha / genetics*
Estrogens / blood*
Female
Genetic Association Studies*
Genotype
Humans
Menstrual Cycle
Norway
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide*
Risk Factors
Saliva
Time Factors

Substances

Estrogen Receptor alpha
Estrogens
Estradiol