Dataset Information

Alcohol consumption and breast tumor gene expression.

ABSTRACT: 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.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.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)-? 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.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.

SUBMITTER: Wang J

PROVIDER: S-EPMC5596493 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Alcohol consumption and breast tumor gene expression.

Wang Jun J Heng Yujing J YJ Eliassen A Heather AH Tamimi Rulla M RM Hazra Aditi A Carey Vincent J VJ Ambrosone Christine B CB de Andrade Victor P VP Brufsky Adam A Couch Fergus J FJ King Tari A TA Modugno Francesmary F Vachon Celine M CM Hunter David J DJ Beck Andrew H AH Hankinson Susan E SE

Breast cancer research : BCR 20170912 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 28899409

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Project description:BackgroundWe investigated the associations of alcohol with percentage of epithelium, stroma, fibroglandular tissue (epithelium + stroma), and fat in benign breast biopsy samples.MethodsWe included 857 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII cohorts. Percentage of each tissue was measured on whole slide images using a deep-learning algorithm and then log-transformed. Alcohol consumption (recent and cumulative average) was assessed with semi-quantitative food frequency questionnaires. Regression estimates were adjusted for known breast cancer risk factors. All tests were 2-sided.ResultsAlcohol was inversely associated with % of stroma and fibroglandular tissue (recent ≥ 22 g/day vs. none: stroma: β = - 0.08, 95% Confidence Interval [CI] - 0.13; - 0.03; fibroglandular: β = - 0.08, 95% CI - 0.13; - 0.04; cumulative ≥ 22 g/day vs. none: stroma: β = - 0.08, 95% CI - 0.13; - 0.02; fibroglandular: β = - 0.09, 95% CI - 0.14; - 0.04) and positively associated with fat % (recent ≥ 22 g/day vs. none: β = 0.30, 95% CI 0.03; 0.57; cumulative ≥ 22 g/day vs. none: β = 0.32, 95% CI 0.04; 0.61). In stratified analysis, alcohol consumption was not associated with tissue measures in premenopausal women. In postmenopausal women, cumulative alcohol use was inversely associated with % of stroma and fibroglandular tissue and positively associated with fat % (≥ 22 g/day vs. none: stroma: β = - 0.16, 95% CI - 0.28; - 0.07; fibroglandular: β = - 0.18, 95% CI - 0.28; - 0.07; fat: β = 0.61, 95% CI 0.01; 1.22), with similar results for recent alcohol use.ConclusionOur findings suggest that alcohol consumption is associated with smaller % of stroma and fibroglandular tissue and a greater % of fat in postmenopausal women. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

Project description:The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.

Dataset Information

Alcohol consumption and breast tumor gene expression.

Publications

Alcohol consumption and breast tumor gene expression.

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