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Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research article

Alcohol consumption and breast tumor gene expression

Authors: Jun Wang, Yujing J. Heng, A. Heather Eliassen, Rulla M. Tamimi, Aditi Hazra, Vincent J. Carey, Christine B. Ambrosone, Victor P. de Andrade, Adam Brufsky, Fergus J. Couch, Tari A. King, Francesmary Modugno, Celine M. Vachon, David J. Hunter, Andrew H. Beck, Susan E. Hankinson

Published in: Breast Cancer Research | Issue 1/2017

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Abstract

Background

Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER)-positive tumors. However, the biological mechanisms underlying this association are not completely understood.

Methods

We analyzed messenger RNA (mRNA) microarray data from both invasive breast tumors (N = 602) and tumor-adjacent normal tissues (N = 508) from participants diagnosed with breast cancer in the Nurses’ Health Study (NHS) and NHSII. Multivariable linear regression, controlling for other known breast cancer risk factors, was used to identify differentially expressed genes by pre-diagnostic alcohol intake. For pathway analysis, we performed gene set enrichment analysis (GSEA). Differentially expressed genes or enriched pathway-defined gene sets with false discovery rate (FDR) <0.1 identified in tumors were validated in RNA sequencing data of invasive breast tumors (N = 166) from The Cancer Genome Atlas.

Results

No individual genes were significantly differentially expressed by alcohol consumption in the NHS/NHSII. However, GSEA identified 33 and 68 pathway-defined gene sets at FDR <0.1 among 471 ER+ and 127 ER- tumors, respectively, all of which were validated. Among ER+ tumors, consuming 10+ grams of alcohol per day (vs. 0) was associated with upregulation in RNA metabolism and transport, cell cycle regulation, and DNA repair, and downregulation in lipid metabolism. Among ER- tumors, in addition to upregulation in RNA processing and cell cycle, alcohol intake was linked to overexpression of genes involved in cytokine signaling, including interferon and transforming growth factor (TGF)-β signaling pathways, and translation and post-translational modifications. Lower lipid metabolism was observed in both ER+ tumors and ER+ tumor-adjacent normal samples. Most of the significantly enriched gene sets identified in ER- tumors showed a similar enrichment pattern among ER- tumor-adjacent normal tissues.

Conclusions

Our data suggest that moderate alcohol consumption (i.e. 10+ grams/day, equivalent to one or more drinks/day) is associated with several specific and reproducible biological processes and pathways, which adds potential new insight into alcohol-related breast carcinogenesis.
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Literature
1.
Jung S, Wang M, Anderson K, Baglietto L, Bergkvist L, Bernstein L, van den Brandt PA, Brinton L, Buring JE, Eliassen AH, et al. Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies. Int J Epidemiol. 2016;45(3):916–28.CrossRefPubMed
2.
Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998;279(7):535–40.CrossRefPubMed
3.
Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):1884–90.CrossRefPubMedPubMedCentral
4.
Li CI, Chlebowski RT, Freiberg M, Johnson KC, Kuller L, Lane D, Lessin L, O'Sullivan MJ, Wactawski-Wende J, Yasmeen S, et al. Alcohol consumption and risk of postmenopausal breast cancer by subtype: the women's health initiative observational study. J Natl Cancer Inst. 2010;102(18):1422–31.CrossRefPubMedPubMedCentral
5.
Dorgan JF, Baer DJ, Albert PS, Judd JT, Brown ED, Corle DK, Campbell WS, Hartman TJ, Tejpar AA, Clevidence BA, et al. Serum hormones and the alcohol-breast cancer association in postmenopausal women. J Natl Cancer Inst. 2001;93(9):710–5.CrossRefPubMed
6.
Reichman ME, Judd JT, Longcope C, Schatzkin A, Clevidence BA, Nair PP, Campbell WS, Taylor PR. Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women. J Natl Cancer Inst. 1993;85(9):722–7.CrossRefPubMed
7.
Seitz HK, Pelucchi C, Bagnardi V, La Vecchia C. Epidemiology and pathophysiology of alcohol and breast cancer: update 2012. Alcohol Alcohol. 2012;47(3):204–12.CrossRefPubMed
8.
Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, et al. A review of human carcinogens − part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 2009;10(11):1033–4.CrossRefPubMed
9.
Castro GD, Delgado de Layno AM, Fanelli SL, Maciel ME, Diaz Gomez MI, Castro JA. Acetaldehyde accumulation in rat mammary tissue after an acute treatment with alcohol. J Appl Toxicol. 2008;28(3):315–21.CrossRefPubMed
10.
Fanelli SL, Maciel ME, Diaz Gomez MI, Delgado de Layno AM, Bietto FM, Castro JA, Castro GD. Further studies on the potential contribution of acetaldehyde accumulation and oxidative stress in rat mammary tissue in the alcohol drinking promotion of breast cancer. J Appl Toxicol. 2011;31(1):11–9.CrossRefPubMed
11.
12.
Fuentes-Mattei E, Velazquez-Torres G, Phan L, Zhang F, Chou PC, Shin JH, Choi HH, Chen JS, Zhao R, Chen J et al. Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. J Natl Cancer Inst. 2014;106(7).
13.
Rotunno M, Sun X, Figueroa J, Sherman ME, Garcia-Closas M, Meltzer P, Williams T, Schneider SS, Jerry DJ, Yang XR, et al. Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status. Breast Cancer Res. 2014;16(4):R74.CrossRefPubMedPubMedCentral
14.
The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.
15.
Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet. 2009;41(5):579–84.CrossRefPubMedPubMedCentral
16.
Tamimi RM, Baer HJ, Marotti J, Galan M, Galaburda L, Fu Y, Deitz AC, Connolly JL, Schnitt SJ, Colditz GA, et al. Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res. 2008;10(4):R67.CrossRefPubMedPubMedCentral
17.
Wang J, Zhang X, Beck AH, Collins LC, Chen WY, Tamimi RM, Hazra A, Brown M, Rosner B, Hankinson SE. Alcohol consumption and risk of breast cancer by tumor receptor expression. Horm Cancer. 2015;6(5–6):237–46.CrossRefPubMedPubMedCentral
18.
Xu W, Seok J, Mindrinos MN, Schweitzer AC, Jiang H, Wilhelmy J, Clark TA, Kapur K, Xing Y, Faham M, et al. Human transcriptome array for high-throughput clinical studies. Proc Natl Acad Sci USA. 2011;108(9):3707–12.CrossRefPubMedPubMedCentral
19.
Kauffmann A, Gentleman R, Huber W. arrayQualityMetrics − a bioconductor package for quality assessment of microarray data. Bioinformatics (Oxford, England). 2009;25(3):415–6.
20.
Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3.
21.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
22.
Wang K, Li M, Hakonarson H. Analysing biological pathways in genome-wide association studies. Nat Rev Genet. 2010;11(12):843–54.CrossRefPubMed
23.
Wang K, Singh D, Zeng Z, Coleman SJ, Huang Y, Savich GL, He X, Mieczkowski P, Grimm SA, Perou CM, et al. MapSplice: accurate mapping of RNA-seq reads for splice junction discovery. Nucleic Acids Res. 2010;38(18):e178.CrossRefPubMedPubMedCentral
24.
Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinforma. 2011;12:323.CrossRef
25.
26.
Romieu I, Scoccianti C, Chajes V, de Batlle J, Biessy C, Dossus L, Baglietto L, Clavel-Chapelon F, Overvad K, Olsen A, et al. Alcohol intake and breast cancer in the European prospective investigation into cancer and nutrition. Int J Cancer. 2015;137(8):1921–30.CrossRefPubMed
27.
Park SY, Kolonel LN, Lim U, White KK, Henderson BE, Wilkens LR. Alcohol consumption and breast cancer risk among women from five ethnic groups with light to moderate intakes: the Multiethnic Cohort Study. Int J Cancer. 2014;134(6):1504–10.CrossRefPubMed
28.
29.
Blackinton JG, Keene JD. Post-transcriptional RNA regulons affecting cell cycle and proliferation. Semin Cell Dev Biol. 2014;34:44–54.CrossRefPubMed
30.
Fan S, Meng Q, Gao B, Grossman J, Yadegari M, Goldberg ID, Rosen EM. Alcohol stimulates estrogen receptor signaling in human breast cancer cell lines. Cancer Res. 2000;60(20):5635–9.PubMed
31.
Singletary KW, Frey RS, Yan W. Effect of ethanol on proliferation and estrogen receptor-alpha expression in human breast cancer cells. Cancer Lett. 2001;165(2):131–7.CrossRefPubMed
32.
Candelaria NR, Weldon R, Muthusamy S, Nguyen-Vu T, Addanki S, Yoffou PH, Karaboga H, Blessing AM, Bollu LR, Miranda RC, et al. Alcohol regulates genes that are associated with response to endocrine therapy and attenuates the actions of tamoxifen in breast cancer cells. PloS One. 2015;10(12):e0145061.CrossRefPubMedPubMedCentral
33.
34.
Dong JT. Anticancer activities of PPARgamma in breast cancer are context-dependent. Am J Pathol. 2013;182(6):1972–5.CrossRefPubMed
35.
Petersen RK, Larsen SB, Jensen DM, Christensen J, Olsen A, Loft S, Nellemann C, Overvad K, Kristiansen K, Tjonneland A, et al. PPARgamma-PGC-1alpha activity is determinant of alcohol related breast cancer. Cancer letters. 2012;315(1):59–68.CrossRefPubMed
36.
Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9(9):631–43.CrossRefPubMed
37.
Santen RJ, Yue W, Wang JP. Estrogen metabolites and breast cancer. Steroids. 2015;99(Pt A):61–6.
38.
39.
Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, Qin L, Szabo G, Wheeler M, Zou J. Cytokines and alcohol. Alcohol Clin Exp Res. 2006;30(4):720–30.CrossRefPubMed
40.
Volpato S, Pahor M, Ferrucci L, Simonsick EM, Guralnik JM, Kritchevsky SB, Fellin R, Harris TB. Relationship of alcohol intake with inflammatory markers and plasminogen activator inhibitor-1 in well-functioning older adults: the Health, Aging, and Body Composition study. Circulation. 2004;109(5):607–12.CrossRefPubMed
41.
Esquivel-Velazquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J. The role of cytokines in breast cancer development and progression. J Interf Cytokine Res. 2015;35(1):1–16.CrossRef
42.
Nicolini A, Carpi A, Rossi G. Cytokines in breast cancer. Cytokine Growth Factor Rev. 2006;17(5):325–37.CrossRefPubMed
43.
Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissiere F, Laune D, Roques S, Lazennec G. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res. 2007;9(1):R15.CrossRefPubMedPubMedCentral
44.
45.
Triano EA, Slusher LB, Atkins TA, Beneski JT, Gestl SA, Zolfaghari R, Polavarapu R, Frauenhoffer E, Weisz J. Class I alcohol dehydrogenase is highly expressed in normal human mammary epithelium but not in invasive breast cancer: implications for breast carcinogenesis. Cancer Res. 2003;63(12):3092–100.PubMed
46.
Kedishvili NY, Stone CL, Popov KM, Chernoff EA. Role of alcohol dehydrogenases in steroid and retinoid metabolism. Adv Exp Med Biol. 1997;414:321–9.CrossRefPubMed
47.
Tang XH, Gudas LJ. Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2011;6:345–64.CrossRefPubMed
48.
Goeman JJ, Buhlmann P. Analyzing gene expression data in terms of gene sets: methodological issues. Bioinformatics (Oxford, England). 2007;23(8):980–7.
49.
Abdueva D, Wing M, Schaub B, Triche T, Davicioni E. Quantitative expression profiling in formalin-fixed paraffin-embedded samples by affymetrix microarrays. J Mol Diagn. 2010;12(4):409–17.CrossRefPubMedPubMedCentral
50.
Ali AM, Schmidt MK, Bolla MK, Wang Q, Gago-Dominguez M, Castelao JE, Carracedo A, Garzon VM, Bojesen SE, Nordestgaard BG, et al. Alcohol consumption and survival after a breast cancer diagnosis: a literature-based meta-analysis and collaborative analysis of data for 29,239 cases. Cancer Epidemiol Biomarkers Prev. 2014;23(6):934–45.CrossRefPubMedPubMedCentral
51.
Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7(8):599–612.CrossRefPubMed
Metadata
Title
Alcohol consumption and breast tumor gene expression
Authors
Jun Wang
Yujing J. Heng
A. Heather Eliassen
Rulla M. Tamimi
Aditi Hazra
Vincent J. Carey
Christine B. Ambrosone
Victor P. de Andrade
Adam Brufsky
Fergus J. Couch
Tari A. King
Francesmary Modugno
Celine M. Vachon
David J. Hunter
Andrew H. Beck
Susan E. Hankinson
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-017-0901-y

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