Abstract 4901: Investigating whether TXNRD2 is a therapeutic target against triple negative breast cancers using African American-derived models

Abstract African American women are twice more likely to be diagnosed with triple negative breast cancer (TNBC) compared to Caucasian women; they are diagnosed with TNBC at a younger age and exhibit a more aggressive disease. TNBC is a heterogenous subtype of breast cancer that does not benefit from targeted therapies thus prognosis remains poor. The increased TNBC incidence and its poor prognosis exacerbate the disparate mortality experienced by African American women diagnosed with breast cancer. Thioredoxin reductases (TXNRDs) are key antioxidant enzymes within the thioredoxin pathway. Most tumors, including TNBCs, express higher levels of antioxidants to cope with higher redox stress resulting from the tumor’s deregulated metabolism and mitogenic stress. This presents a therapeutic vulnerability and TXNRD1, the cytoplasmic isoform, is proposed as a cancer therapeutic target. TXNRD2 is the mitochondrial isoform; its contribution to cancer progression is understudied and unclear. Our investigation into breast cancer patient databases (Clinical Proteomic Tumor Analysis Consortium, CPTAC) demonstrated that African American patients have elevated levels of TXNRD2. Based on these observations, our goal is to (i) investigate whether TXNRD2 is a therapeutic target against TNBC using African American-derived cell models, and (ii) determine whether a new class of TXNRD inhibitors in development by us, TXNRD(i)s, can be effective drugs against aggressive TNBC. If successful, our work will set the stage for developing new drugs that are highly needed for treating TNBC in the clinic and may reduce the racial disparity gap in breast cancer. A panel of African American derived TNBC cell lines were characterized by western blot for expression levels of TXNRD1 and 2. HCC1806 cells, which had elevated levels of TXNRD2, were transfected with siTXNRD2 or control and cell growth was monitored over 5 days. Silencing of TXNRD2 significantly attenuated cell growth. Treatment of these cells with TXNRD(i)s inhibited cell viability in vitro and in vivo using a xenograft model. To determine to what extent, the inhibition of TXNRD2 vs TXNRD1 by TXNRD(i)s contributes to the anti-cancer activity we are optimizing a fluorescent probe and live cell imaging by microscopy. HCC1806 cells were incubated with TRFS-Green which fluoresces upon reduction by TXNRDs and MitoTracker-Red which stains for mitochondria where TXNRD2 is located. Colocalization between TRFS-Green and MitoTracker-Red indicates TXNRD2 specific activity. Novel TXNRD(i)s are being catalogue for TXNRD specific inhibition. Together our data support the development of TXNRD2 inhibitors to treat African American women with TNBC. Citation Format: Keacha Chang, Brenna Flowers, Abigail Rullo, Irida Kastrati. Investigating whether TXNRD2 is a therapeutic target against triple negative breast cancers using African American-derived models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4901.