Abstract 1439: NUDT5 is a critical regulator of triple-negative breast cancer growth

Abstract

Abstract Background: Triple-negative breast cancers (TNBC) represent 15% of all breast cancers, and are highly aggressive cancers with poor clinical outcome. We have previously conducted a whole phosphatase RNA microarray analysis of TNBCs compared to estrogen receptor (ER)-positive breast cancers. These studies identified phosphatases that were either over-expressed or under-expressed in TNBCs as compared to ER-positive breast cancers. One of the phosphatases highly expressed in TNBCs was NUDT5, which hydrolyzes 8-oxo-dGDP and ADP-ribose (ADPR). Recent studies have shown that NUDT5 regulates cell cycle progression, and increases cellular ATP in response to hormone stimulation in cancer cells. However, the biological function of NUDT5 in TNBCs is largely unknown. Hypothesis: We hypothesized that NUDT5 is a critical phosphatase over-expressed in TNBCs that regulates the growth of these breast cancer cells. Methods: We analyzed TNBC NUDT5 mRNA expression and clinical outcome using publicly available TCGA, METABRIC, and the CCLE datasets. Overall survival was evaluated using Kaplan-Meier curves and compared using log-rank analysis (* p<0.05). We next conducted siRNA knockdown studies using DharmaFECT transfection, and subsequently measured the effect on growth using automated cell counting. Results at day 7 were expressed as mean cell numbers +/- standard deviation, and analyzed using Student's t-tests. Results: Analysis of NUDT5 mRNA expression demonstrated that NUDT5 is overexpressed in triple-negative breast cancers, specifically in the basal-like subtype of TNBC. Analysis of publically available breast cancer datasets showed that high NUDT5 expression is associated with poor overall survival of breast cancer patients. Knockdown of NUDT5 decreased TNBC growth, but did not decrease the growth of non-TNBC cells. Conclusions: Our results demonstrate that NUDT5 is a critical regulator of TNBC growth, and raise the possibility of targeting this critical phosphatase for the treatment of TNBC tumors. Future studies will investigate the function of NUDT5 in regulating nucleotide pool metabolism in TNBCs. Understanding the role of NUDT5 in controlling TNBC growth will provide the basic science foundation for the future development of NUDT5 inhibitors for the treatment of women with these aggressive, potentially life-threatening cancers. This work was supported by Susan G Komen Promise Grant (PB), and the John Charles Cain Endowment (PB). Citation Format: Jing Qian, William Tahaney, Yanxia Ma, Lakshmi Bollu, Abhijit Mazumdar, Jamal Hill, Yun Zhang, Powel Brown. NUDT5 is a critical regulator of triple-negative breast cancer growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1439.