Abstract PO-131: RAD51 is a biomarker for aggressive disease and racial disparities in triple-negative breast cancer

Abstract

Abstract Breast cancer (BC) is the second most diagnosed malignant disease in women, and one of the leading causes of cancer-related deaths. Triple-negative breast cancer (TNBC) is the most aggressive and difficult to treat subtype of BC because it is highly metastatic and lacks targeted therapies. African American (AA) women have a higher death rate from BC than 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 studies identified that multiple TNBC cells derived from AA women are inherently chemoresistant and exhibit aggressive growth behavior compared to TNBC cells derived from European American (EA) patients. Our preliminary screenings showed that the DNA repair protein, RAD51, is overexpressed in AA TNBC patients and correlates a poor prognosis relative to EA TNBC patients. Analysis of AA and EA TNBC tumor specimens indicated the epigenetic regulation of RAD51 by promoter methylations and microRNAs. Furthermore, AA women diagnosed with TNBC, have a considerably lower incidence of germline BRCA1 mutations than women of other racial or ethnic groups. This indicates most TNBC tumors in AA patients are DNA repair proficient and have intact cell cycle checkpoint mechanisms that protect them from chemotherapy-induced DNA damage and promote therapeutic resistance. Our drug screenings identified CHK1 inhibitor, Prexasertib caused DNA repair deficiency in BRCA wild-type TNBC cells by promoting proteasome-mediated degradation of BRCA1 and RAD51 proteins. Therefore, we designed a synthetic lethality-based drug combination of Prexasertib with PARP inhibitors (PARPi) in DNA repair proficient TNBC cells. Data from our preclinical evaluations show Prexasertib and Olaparib cause increased DNA strand breaks, mitotic catastrophe, and synergistic TNBC cell lethality compared to individual drug treatments. Additionally, computational analysis of TCGA data revealed a RAD51 upregulation in TNBC tumors compared to normal breast tissues and other subtypes of BC which renders as a poor prognostic marker for these patients. Remarkably, there was an interesting discrepancy in RAD51 expression levels between different racial groupings, with AA and Asian BC patients having higher levels of RAD51 expression than Caucasian BC patients. Consistent with these observations, AA and Asian TNBC patients showed decreased survival probability. Together, our data indicate that RAD51 and its epigenetic regulators could be biomarkers for aggressive TNBC and racial disparity in BC therapeutic outcomes and suggests a novel combination therapy involving Prexasertib and Olaparib may improve prognosis and reduce racial disparity in TNBC. Citation Format: Ganesh N. Acharya, Chinnadurai Mani, Upender Manne, Komaraiah Palle. RAD51 is a biomarker for aggressive disease and racial disparities in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-131.