Abstract B18: ADSL controls pyrimidine metabolism and triple-negative breast tumorigenesis

Abstract

Triple-negative breast cancer (TNBC) represents 15% of all breast carcinomas. The unfavorable prognosis and aggressive biology of TNBC highlight the need to find new targeted therapies. Previous study from our lab has shown that the prolyl hydroxylase EglN2 contributes to TNBC progression, with its depletion leading to a decrease in TNBC cell invasion. However, the underlying mechanism remains elusive. In our current study, we developed a novel enzyme-substrate trapping strategy followed by mass spectrometry and identified adenylosuccinate lyase (ADSL) as a potential EglN2 hydroxylase substrate. EglN2 binds directly with ADSL and catalyzes ADSL hydroxylation on proline residues, which might affect ADSL activity. We demonstrated that ADSL is specifically upregulated in TNBC cell lines and patients. Functionally, depletion of ADSL led to decreased anchorage-independent growth, TNBC cell invasion, and orthotopic tumor growth. Mechanistically, integrated analyses of metabolomics and RNA-seq showed that ADSL controls pyrimidine biosynthesis that is essential for TNBC cell proliferation and invasion. Therefore, our study suggests that EglN2-ADSL signaling axis can serve as a novel therapeutic avenue in TNBC by regulating pyrimidine metabolism. Citation Format: Giada Zurlo, Jeremy Simon, Cheng Fan, Adam Robinson, Javier Rodriguez Martinez, Alex Kriegsheim, Jason Locasale, Charles Perou, Qing Zhang. ADSL controls pyrimidine metabolism and triple-negative breast tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B18.