饮酒与乳腺癌基因表达。
Alcohol consumption and breast tumor gene expression.
机构信息
Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, 715 N Pleasant Street, Amherst, MA, 01003, USA.
Present address: Department of Preventive Medicine, University of Southern California, Harlyne J. Norris Research Tower, 1450 Biggy Street, Los Angeles, CA, 90033, USA.
出版信息
Breast Cancer Res. 2017 Sep 12;19(1):108. doi: 10.1186/s13058-017-0901-y.
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.
背景
饮酒是乳腺癌的既定风险因素，这种关联在雌激素受体（ER）阳性肿瘤中似乎更为明显。然而，这种关联的生物学机制尚不完全清楚。
方法
我们分析了来自参加护士健康研究（NHS）和 NHSII 的乳腺癌患者的浸润性乳腺癌肿瘤（N=602）和肿瘤相邻正常组织（N=508）的信使 RNA（mRNA）微阵列数据。使用多变量线性回归，控制其他已知的乳腺癌风险因素，鉴定了通过预诊断性饮酒摄入差异表达的基因。为了进行途径分析，我们进行了基因集富集分析（GSEA）。在 NHS/NHSII 中，没有发现个体基因因饮酒而显著差异表达。然而，GSEA 在 471 个 ER+和 127 个 ER-肿瘤中鉴定出 FDR<0.1 的 33 和 68 个通路定义的基因集，所有这些基因集都得到了验证。在 ER+肿瘤中，每天饮用 10 克以上酒精（vs. 0 克）与 RNA 代谢和运输、细胞周期调节和 DNA 修复上调，以及脂质代谢下调相关。在 ER-肿瘤中，除了 RNA 处理和细胞周期的上调外，饮酒还与细胞因子信号、包括干扰素和转化生长因子（TGF）-β信号通路以及翻译和翻译后修饰的相关基因的过度表达相关。在 ER+肿瘤和 ER+肿瘤相邻的正常样本中都观察到脂质代谢降低。在 ER-肿瘤中鉴定的大多数显著富集基因集在 ER-肿瘤相邻的正常组织中表现出相似的富集模式。
结论
我们的数据表明，适度饮酒（即每天 10 克以上，相当于每天 1 或更多饮料）与几个特定且可重复的生物学过程和途径相关，这为酒精相关的乳腺癌发生提供了潜在的新见解。
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