Novel Predictors of Breast Cancer Survival Derived from miRNA Activity Analysis

Abstract

<b>Purpose:</b> Breast cancer is among the leading causes of cancer-related death; discovery of novel prognostic markers is needed to improve outcomes. Combining systems biology and epidemiology, we investigated miRNA-associated genes and breast cancer survival in a well-characterized population-based study.<b>Experimental Design:</b> A recently developed algorithm, <i>ActMiR</i>, was used to identify key miRNA "activities" corresponding to target gene degradation, which were predictive of breast cancer mortality in published databases. We profiled miRNA-associated genes in tumors from our well-characterized population-based cohort of 606 women with first primary breast cancer. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI), after 15+ years of follow-up with 119 breast cancer-specific deaths.<b>Results:</b> miR-500a activity was identified as a key miRNA for estrogen receptor-positive breast cancer mortality using public databases. From a panel of 161 miR-500a-associated genes profiled, 73 were significantly associated with breast cancer-specific mortality (FDR < 0.05) in our population, among which two clusters were observed to have opposing directions of association. For example, high level of <i>SUSD3</i> was associated with reduced breast cancer-specific mortality (HR = 0.3; 95% CI, 0.2-0.4), whereas the opposite was observed for <i>TPX2</i> (HR = 2.7; 95% CI, 1.8-3.9). Most importantly, we identified set of genes for which associations with breast cancer-specific mortality were independent of known prognostic factors, including hormone receptor status and PAM50-derived risk-of-recurrence scores. These results are validated in independent datasets.<b>Conclusions:</b> We identified novel markers that may improve prognostic efficiency while shedding light on molecular mechanisms of breast cancer progression. <i>Clin Cancer Res; 24(3); 581-91. ©2017 AACR</i>.