Exploiting Amino Acid Catabolism as a Metabolic Vulnerability in Breast Cancer

Abstract

A growing tumor is faced with many challenges, including how to obtain and utilize nutrients. Reprogramming of metabolism has emerged as a hallmark of cancer and numerous studies have identified specific alterations in metabolic pathways in tumors and how they can lead to targetable vulnerabilities. This thesis investigates the metabolism of triple-negative breast cancer (TNBC), a disease where treatment is limited by a lack of effective molecularly targeted therapies. We have focused on the effects of genotoxic chemotherapy drugs on the metabolism of the amino acid arginine. First, we investigated how chemotherapy drugs alter the levels of metabolites and enzymes involved in arginine metabolism. We found that exposure of TNBC cells in vitro to cytotoxic chemotherapy drugs leads to alterations in polyamines due to a reduction in the levels and activity of the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase (ODC). We also observed this decrease in ODC in receptor-positive breast cancer cells, suggesting that it is widespread. The reduction in ODC was mediated by its negative regulator, antizyme, targeting ODC to the proteasome for degradation. Secondly, we investigated the efficacy of targeting polyamine synthesis as an anti-cancer strategy in TNBC. We found that the ODC inhibitor DFMO increased killing of TNBC cells in combination with chemotherapy or alone, and ODC levels were elevated in TNBC patient samples. Alterations in polyamine metabolism in response to chemotherapy, as well as preferential sensitization of TNBC cells to chemotherapy by DFMO, suggest that ODC may be a targetable metabolic vulnerability in TNBC. Together, the data in this thesis highlight novel alterations and potential therapeutic targets in arginine and polyamine metabolism in TNBC.