Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women

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Abstract

Introduction

High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women.

Methods

Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models.

Results

The minor alleles of rs749292 were positively ( P = 0.026), and the minor alleles of rs7172156 were inversely ( P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m ²) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density ( P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm ²); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density ( aa: OR = 5.45 (95% CI 1.13 to 26.3)).

Conclusion

Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-014-0499-2) contains supplementary material, which is available to authorized users.

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Most cited references 54

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Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.

Christopher Carlson, Michael A Eberle, Mark J. Rieder … (2004)

Common genetic polymorphisms may explain a portion of the heritable risk for common diseases. Within candidate genes, the number of common polymorphisms is finite, but direct assay of all existing common polymorphism is inefficient, because genotypes at many of these sites are strongly correlated. Thus, it is not necessary to assay all common variants if the patterns of allelic association between common variants can be described. We have developed an algorithm to select the maximally informative set of common single-nucleotide polymorphisms (tagSNPs) to assay in candidate-gene association studies, such that all known common polymorphisms either are directly assayed or exceed a threshold level of association with a tagSNP. The algorithm is based on the r(2) linkage disequilibrium (LD) statistic, because r(2) is directly related to statistical power to detect disease associations with unassayed sites. We show that, at a relatively stringent r(2) threshold (r2>0.8), the LD-selected tagSNPs resolve >80% of all haplotypes across a set of 100 candidate genes, regardless of recombination, and tag specific haplotypes and clades of related haplotypes in nonrecombinant regions. Thus, if the patterns of common variation are described for a candidate gene, analysis of the tagSNP set can comprehensively interrogate for main effects from common functional variation. We demonstrate that, although common variation tends to be shared between populations, tagSNPs should be selected separately for populations with different ancestries.

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Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.

T Key, P Appleby, I. Barnes … (2002)

Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.

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Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer.

Patrick Morris, Clifford Hudis, Dilip Giri … (2011)

Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. In humans, obesity causes subclinical inflammation in visceral and subcutaneous adipose tissue, characterized by necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS). Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, and elevated aromatase levels and activity in the mammary glands of obese mice. These preclinical findings raised the possibility that the obesity → inflammation axis is important for the development and progression of breast cancer. Here, our main objective was to determine if the findings in mouse models of obesity translated to women. Breast tissue was obtained from 30 women who underwent breast surgery. CLS of the breast (CLS-B) was found in nearly 50% (14 of 30) of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index (P < 0.001) and adipocyte size (P = 0.01). Increased NF-κB binding activity and elevated aromatase expression and activity were found in the inflamed breast tissue of overweight and obese women. Collectively, our results suggest that the obesity → inflammation → aromatase axis is present in the breast tissue of most overweight and obese women. The presence of CLS-B may be a biomarker of increased breast cancer risk or poor prognosis.

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Author and article information

Contributors

Vidar G Flote: v.g.flote@medisin.uio.no

Anne-Sofie Furberg: anne-sofie.furberg@uit.no

Anne McTiernan: amctiern@fhcrc.org

Hanne Frydenberg: hanne.frydenberg@medisin.uio.no

Giske Ursin: giske.ursin@kreftregisteret.no

Anita Iversen: anita.iversen@uit.no

Trygve Lofteroed: loftry@ous-hf.no

Peter T Ellison: pellison@fas.harvard.edu

Erik A Wist: erik.wist@medisin.uio.no

Thore Egeland: thore.egeland@nmbu.no

Tom Wilsgaard: tom.wilsgaard@uit.no

Karen W Makar: kmakar@fhcrc.org

Jenny Chang-Claude: j.chang-claude@dkfz-heidelberg.de

Inger Thune: inger.thune@uit.no

Journal

Journal ID (nlm-ta): Breast Cancer Res

Title: Breast Cancer Research : BCR

Publisher: BioMed Central (London )

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Electronic): 19 December 2014

Publication date PMC-release: 19 December 2014

Publication date (Print): 2014

Volume: 16

Issue: 6

Electronic Location Identifier: 499

Affiliations

[ ]The Cancer Centre, Oslo University Hospital, Oslo, N-0424 Norway

[ ]Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, N-9037 Norway

[ ]Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA 98109-1024 USA

[ ]Cancer Registry of Norway, PO Box 5313, Majorstuen, Oslo, N-0304 Norway

[ ]Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, N-9037 Norway

[ ]Department of Anthropology, Harvard University, Cambridge, MA 02138 USA

[ ]Department of Chemistry, Norwegian University of Life Sciences, Biotechnology and Food Science, Aas, N-1432 Norway

[ ]Unit of Genetic Epidemiology, Division of Cancer Epidemiology, Deutches Krebsforschungszentrum, 69120 Heidelberg, Germany

Article

Publisher ID: 499

DOI: 10.1186/s13058-014-0499-2

PMC ID: 4303212

PubMed ID: 25522654

SO-VID: a25c8256-21ce-4849-a959-2186a3da1937

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 24 June 2014

Date accepted : 8 December 2014

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ScienceOpen disciplines: Oncology & Radiotherapy

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ScienceOpen disciplines: Oncology & Radiotherapy

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Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women

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Abstract

Introduction

Methods

Results

Conclusion

Electronic supplementary material

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Karger: Oncology

Most cited references 54

Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.

Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.

Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer.

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Contributors

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