Abstract B75: Nutritional profiling reveals glutamine-utilizing transaminases as a metabolic vulnerability of TAZ/YAP-driven breast cancer cells

The aberrant activity of the transcriptional regulators TAZ and YAP (TAZ/YAP) drives many oncogenic traits, including the resistance to cell death, sustaining cell growth, and control of cell fate. Aggressive breast cancers in particular exhibit high TAZ/YAP levels and activity, and thus understanding the roles of these factors may offer therapeutic opportunity for these poorly treatable diseases. Here, we report that TAZ/YAP play an important role in driving breast cancer dependency to exogenous glutamine, an abundant amino acid that has emerged as central for tumor growth. We observed that breast cancer cells with high levels of TAZ/YAP are more sensitive to glutamine deprivation, and that knockout of TAZ/YAP in these cells alleviated defects resulting from glutamine. Rescue experiments with glutamine-derived metabolites suggested an essential role for glutamate and α-ketoglutarate (AKG) in TAZ/YAP-driven cell growth. Analysis of enzymes mediating the conversion of glutamate to α-ketoglutarate (AKG) showed that TAZ/YAP induce the expression of distinct transaminases, and that TAZ/YAP activity positively correlates with transaminase expression in breast cancer patients. Notably, the transaminase inhibitor aminooxyacetate (AOA) repressed cell growth in a TAZ/YAP-dependent manner, identifying transamination as a potential vulnerable metabolic requirement for TAZ/YAP-driven breast cancer. Considering the link between breast cancer risk and obesity, and the connection between obesity-driven metabolic changes to glutamine metabolism, our study offers a potential direction for future therapeutic targeting of aggressive breast cancers in underserved populations, where obesity is becoming a prevalent factor. Citation Format: Eleni Stampouloglou, Nathan Kingston, Chih-Sheng Yang, Liye Zhang, Stefano Monti, Xaralabos Varelas. Nutritional profiling reveals glutamine-utilizing transaminases as a metabolic vulnerability of TAZ/YAP-driven breast cancer cells [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B75.