Abstract
BackgroundAlcohol 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.MethodsWe 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.ResultsNo 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.ConclusionsOur 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.
Highlights
Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER)-positive tumors
To help unravel the underlying mechanisms of alcohol consumption and breast cancer risk, we evaluated the association between pre-diagnostic alcohol consumption and genome-wide gene expression in breast tumor and tumor-adjacent normal tissue in the prospective Nurses’ Health Study (NHS) and NHSII, and further validated our results in an independent validation dataset obtained from The Cancer Genome Atlas (TCGA) [14]
Only a subset of all the eligible cases were included in the TMA, in each cohort, the characteristics of participants included in the TMA were very similar to those of all the eligible cases, including alcohol consumption and other breast cancer risk factors
Summary
Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER)-positive tumors. Alcohol consumption is an established breast cancer risk factor [1]. The mechanism underlying the alcohol and breast cancer association is not completely understood. Acetaldehyde has been classified as a carcinogen by the International Agency for Research on Cancer (IARC) [8] and, after alcohol administration, accumulation of acetaldehyde was observed in rat mammary tissue in experimental studies [9, 10]. Disruption of folate metabolism and DNA and/or histone hypomethylation have been hypothesized to be involved in alcohol-mediated carcinogenesis [8]. Despite these hypotheses, no definitive mechanisms have yet been identified
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