Purpose: Compared with their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor–positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation. Experimental Design: Data and biospecimens from 262 AA and 293 EA patients diagnosed with breast cancer from 2001 to 2010 at a major medical center were analyzed by IHC for functional biomarkers of luminal differentiation, including estrogen receptor ( ESR1 ) and its pioneer factors, FOXA1 and GATA3 . Integrated comparison of protein levels with network-level gene expression analysis uncovered predictive correlations with race and survival. Results: Univariate or multivariate HRs for overall survival, estimated from digital IHC scoring of nuclear antigen, show distinct differences in the magnitude and significance of these biomarkers to predict survival based on race: ESR1 [EA HR = 0.47; 95% confidence interval (CI), 0.31–0.72 and AA HR = 0.77; 95% CI, 0.48–1.18]; FOXA1 (EA HR = 0.38; 95% CI, 0.23–0.63 and AA HR = 0.53; 95% CI, 0.31–0.88), and GATA3 (EA HR = 0.36; 95% CI, 0.23–0.56; AA HR = 0.57; CI, 0.56–1.4). In addition, we identify genes in the downstream regulons of these biomarkers highly correlated with race and survival. Conclusions: Even within clinically homogeneous tumor groups, regulatory networks that drive mammary luminal differentiation reveal race-specific differences in their association with clinical outcome. Understanding these biomarkers and their downstream regulons will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer survival.

中文翻译：

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Luminal 主调节基因表达水平与乳腺癌存活率之间关系的种族差异


目的：与欧洲裔美国人 (EA) 女性相比，非裔美国 (AA) 女性在美国死于乳腺癌的可能性更高。这种差异在激素受体阳性亚型中最为明显。在这里，我们通过比较管腔分化的主转录调节因子的功能表达和预后意义，揭示了这种差异背后的生物学因素。实验设计：通过 IHC 分析了 2001 年至 2010 年在一家大型医疗中心诊断为乳腺癌的 262 名 AA 和 293 名 EA 患者的数据和生物样本，以了解管腔分化的功能性生物标志物，包括雌激素受体 (ESR1) 及其先锋因子、FOXA1 和伽塔3。蛋白质水平与网络水平基因表达分析的综合比较揭示了与种族和生存的预测相关性。结果：根据核抗原的数字 IHC 评分估算的总生存期的单变量或多变量 HR，显示出这些生物标志物在基于种族预测生存期的大小和显着性上存在显着差异：ESR1 [EA HR = 0.47；EA HR = 0.47； 95% 置信区间 (CI)，0.31–0.72，AA HR = 0.77； 95% CI，0.48–1.18]； FOXA1（EA HR = 0.38；95% CI，0.23–0.63；AA HR = 0.53；95% CI，0.31–0.88）和 GATA3（EA HR = 0.36；95% CI，0.23–0.56；AA HR = 0.57；置信区间，0.56–1.4）。此外，我们还确定了这些生物标志物下游调节子中与种族和生存高度相关的基因。结论：即使在临床同质的肿瘤组中，驱动乳腺管腔分化的调节网络也揭示了其与临床结果的关联的种族特异性差异。 了解这些生物标志物及其下游调节子将阐明导致乳腺癌生存率种族差异的内在机制。