Abstract PO-056: Role of the metabolite N-acetylaspartate in breast cancer progression

Abstract Breast cancer (BCa) is a disease that affects over a quarter million women in the US every year. Our laboratory studies reprogrammed energy metabolism in BCa, which is an essential hallmark of the disease. Specifically, we focus on the metabolic rewiring events that occur in BCa, intending to identify cancer-associated metabolic vulnerabilities to treat this aggressive disease. Using a global metabolic profiling approach, we have determined that the metabolite N-acetylaspartate (NAA) is highly accumulated in patients with BCa. Prior studies involving NAA in other cancer types have attributed its accumulation to the upregulation of the enzyme N-acetyl transferase (NAT8L), which synthesizes NAA. However, using matched gene expression data, we found that the accumulation of NAA in these BCa tumors rather coincides with the downregulation of aspartoacylase (ASPA), the enzyme that breaks down NAA. To determine the role of NAA in BCa progression, we generated multiple cell line models containing either NAT8L knockdown, ASPA overexpression, or a combination of the two in the cell line MDA-MB231 in a bid to deplete intracellular NAA. We used these models to test for metastasis by tail vein injection in immunocompromised mice. Consistent with our expectations and other reports, NAT8L knockdown resulted in reduced lung metastasis. Interestingly, however, NAA depletion via ASPA overexpression increased metastasis to the lung in vivo. Furthermore, the combination of ASPA overexpression with the knockdown of NAT8L led to a moderate phenotype between the two independent genetic modifications. Our findings of the metastasis-promoting effect of NAA depletion via ASPA overexpression leads to us believe that it is not just the accumulation of NAA but also its utilization that is important for breast cancer progression. Our future experiments are directed towards determining how NAA utilization causes a pro-tumorigenic phenotype. We would also like to study the current inconsistency between ASPA transcript levels in patient tumors and its observed tumor-promoting function in xenograft experiments. Completion of these studies will potentially define the importance of elevated NAA levels in the context of aggressive BCa. Since NAA is a metabolite that can be detected in serum, our study could also lead to the development of NAA as a non-invasive biomarker for early detection of aggressive BCa, thus providing a bigger window for therapeutic intervention. Citation Format: Akhila Balasubramanian, Weijie Zhang, Franklin Gu, Chandra Ambati, Nagireddy Putluri, Xiang Zhang, Aryan Namboodiri, Stefan Ambs, Arun Sreekumar. Role of the metabolite N-acetylaspartate in breast cancer progression [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-056.