Abstract 1444: RhoC regulation of inflammatory breast cancer metabolism

Abstract

Abstract Inflammatory breast cancer (IBC) is an extremely aggressive and lethal type of cancer due to its ability to rapidly metastasize. Our previous reports have shown that the metabolic characteristics of IBC are altered from those of normal breast epithelial cells. Specifically, the levels of the metabolite N-acetylaspartate (NAA) are very high in the IBC-derived triple negative cell line SUM149 relative to the triple negative cancer cell line MDA-MB-231. Recent studies have also correlated high levels of tumoral NAA with significantly lower survival rates in ovarian cancer. N-acetylaspartate (NAA) is the second most abundant metabolite in the brain, only exceeded by glutamate. NAA is synthesized from aspartate and acetyl-CoA by the enzyme Asp-NAT, which is encoded for by the gene NAT8L. The catabolism of NAA to aspartate and acetate is carried out by the enzyme aspartoacyclase (ASPA). In the central nervous system (CNS), altered levels of NAA have been historically used as a marker for neurodegenerative diseases such as Canavan disease, a fatal genetic disorder caused by a deleterious mutation in the ASPA gene. However, the fundamental role of NAA, especially in the context of cancer remains elusive. We seek to understand and describe the role of NAA in the adapted metabolic pathways of inflammatory breast cancer that enable proliferation and metastasis of the disease. Our previous work revealed that the pro-metastatic small GTPase RhoC acts as a regulator of NAA metabolism in SUM149 cells. Knockdown of RhoC using shRNA significantly decreases NAT8L expression. RhoC and RhoA knockout cell lines have been generated using CRIPSR-Cas9 in both SUM149 and MDA-MB-231 cells to further distinguish the relationship between NAA and RhoC in these different cell lines. We have conducted metabolic studies to determine the relative abundance of common metabolites, including NAA, throughout glycolysis, the pentose-phosphate pathway, and the tricarboxylic acid cycle. We have performed similar metabolomics using xenograft mice implanted with these CRISPR knockout cell lines to determine in vivo recapitulation of the NAA phenotypes. Our work ultimately hopes to identify promising therapeutic pathways of NAA as well as further characterize NAA's role as a potential oncometabolite. Citation Format: Laura E. Goo, Joel A. Yates, Liwei Bao, Zhifen Wu, Sofia D. Merajver. RhoC regulation of inflammatory breast cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1444.