Racial Differences in the Association between Luminal Master Regulator Gene Expression Levels and Breast Cancer Survival

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Clinical cancer research


PURPOSE: Compared to 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 2001-2010 at a major medical center, were analyzed by immunohistochemistry (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 hazard ratios (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% CI: 0.31-0.72; AA HR= 0.77, CI: 0.48-1.18); FOXA1 (EA HR= 0.38, CI: 0.23-0.63; AA HR = 0.53, CI: 0.31-0.88); and GATA3 (EA HR= 0.36, CI: 0.23-0.56; AA HR= 0.57, CI: 0.56-1.4). Additionally, 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.

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ePub ahead of print