Healey Megan A, Hu Rong, Beck Andrew H, Collins Laura C, Schnitt Stuart J, Tamimi Rulla M, Hazra Aditi
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Breast Cancer Res Treat. 2014 Oct;147(3):639-51. doi: 10.1007/s10549-014-3089-1. Epub 2014 Sep 16.
Repressive histone tail modifications have been associated with molecular breast cancer subtypes. We investigated whether histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) were associated with tumor features and subtypes while adjusting for prospectively collected reproductive and lifestyle breast cancer risk factors. We have tissue microarray data with immunohistochemical marker information on 804 incident cases of invasive breast cancer diagnosed from 1976-2000 in the Nurses' Health Study. Tissue microarray sections were stained for global H3K9me3 and H3K27me3, and scored into four categories. Multivariate odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression models for tumor features and subtypes, adjusting for breast cancer risk factors. While there were no significant associations between H3K9me3 and tumor features, H3K27me3 was significantly associated with lower grade tumors compared to high grade tumors in the multivariate model (OR = 1.95, 95 % CI 1.35-2.81, p = 0.0004). H3K27me3 was suggestively associated with estrogen receptor-positive (ER+) tumors (OR = 1.47, 95 % CI 0.97-2.23, p = 0.07). In subtype analyses, H3K27me3 was positively associated with the luminal A subtype compared to all other subtypes (OR = 1.42, 95 % CI 1.14-1.77, p = 0.002), and was inversely associated with HER2-type (OR = 0.58, 95 % CI 0.37-0.91, p = 0.02) and basal-like breast cancer (OR = 0.52, 95 % CI 0.36-0.76, p = 0.0006). In the largest immunohistochemical examination of H3K9me3 and H3K27me3 in breast cancer, we found that H3K27me3 positivity, but not H3K9me3, was associated with lower grade tumors and the luminal A subtype after adjusting for reproductive and lifestyle breast cancer risk factors.
组蛋白尾部的抑制性修饰与乳腺癌分子亚型相关。我们研究了组蛋白3赖氨酸9三甲基化（H3K9me3）和组蛋白3赖氨酸27三甲基化（H3K27me3）是否与肿瘤特征及亚型相关，同时对前瞻性收集的生殖和生活方式相关的乳腺癌风险因素进行了校正。在护士健康研究中，我们有1976年至2000年诊断的804例浸润性乳腺癌病例的组织芯片数据及免疫组化标志物信息。组织芯片切片进行了整体H3K9me3和H3K27me3染色，并分为四类。使用逻辑回归模型计算肿瘤特征及亚型的多变量优势比（OR）和95%置信区间（CI），并对乳腺癌风险因素进行校正。虽然H3K9me3与肿瘤特征之间无显著关联，但在多变量模型中，与高级别肿瘤相比，H3K27me3与低级别肿瘤显著相关（OR = 1.95，95% CI 1.35 - 2.81，p = 0.0004）。H3K27me3与雌激素受体阳性（ER +）肿瘤有提示性关联（OR = 1.47，95% CI 0.97 - 2.23，p = 0.07）。在亚型分析中，与所有其他亚型相比，H3K27me3与管腔A型亚型呈正相关（OR = 1.42，95% CI 1.14 - 1.77，p = 0.002），与HER2型（OR = 0.58，95% CI 0.37 - 0.91，p = 0.02）和基底样乳腺癌（OR = 0.52，95% CI 0.36 - 0.76，p = 0.0006）呈负相关。在对乳腺癌中H3K9me3和H3K27me3进行的最大规模免疫组化检查中，我们发现，在校正生殖和生活方式相关的乳腺癌风险因素后，H3K27me3阳性而非H3K9me3阳性与低级别肿瘤和管腔A型亚型相关。
