Abstract C027: miRNA-214-5P regulates RAD51, a biomarker for aggressive disease and racial disparities in triple-negative breast cancer

Abstract

Abstract Breast cancer (BC) is one of the deadliest cancers in women. Among various subtypes, triple-negative breast cancer (TNBC) is the most aggressive and hard to treat subtype of breast cancer because it is highly metastatic and lacks targeted therapies. The death rate from BC is higher among African American (AA) women than among women of other races and ethnicities. The higher incidences of TNBCs and their aggressive growth in young AA women contributing to higher death rates indicate a biological basis for this difference. Thus, it is imperative to understand the molecular mechanisms that contribute to aggressive tumor growth in AA women, identify biomarkers to select patients who will respond to existing therapies, and develop effective therapeutics to reduce this disparity. Our previous findings showed that the DNA repair protein, RAD51, is overexpressed in AA TNBC patients and correlates with a poor prognosis relative to European American (EA) TNBC patients. However, the exact mechanism behind the regulation of RAD51 has not been identified. Our miRNA seq analysis shows a list of downregulated miRNAs in AA TNBC cell lines compared to EA TNBC cell lines. Interestingly, the miRDB-MicroRNA Target Prediction Database predicted that miR-214-5P has the seed sequence to bind and degrade RAD51 mRNA. Analysis of the TCGA database by UALCAN portal also shows a decreased expression of miR-214-5P in AA TNBC patients compared to EA TNBC patients. Treating the AA TNBC cell lines with miR-214-5P mimic downregulates RAD51 expression in a cell cycle-independent manner and also induces HR-deficiency as measured by Dr-GFP assay. Based on these results, we designed a synergistic lethality-based combination of miR-214-5P and Olaparib in TNBC cells. Data from our preclinical evaluations show miR-214-5P and Olaparib cause increased DNA strand breaks, and synergistic TNBC cell lethality compared to individual treatments. Together, our data indicate that miR-214-5P regulates RAD51 and either of these genes could be biomarkers for aggressive TNBC and racial disparity in BC therapeutic outcomes. Citation Format: Ganesh Acharya, Chinnadurai Mani, Upender Manne, Komaraiah Palle. miRNA-214-5P regulates RAD51, a biomarker for aggressive disease and racial disparities in triple-negative breast cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C027.