Search for alternative anaplerotic sources of the TCA as new targets against triple-negative breast cancer

• Grant number: 13/12186-1
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2013
• End date: February 28, 2015
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Sandra Martha Gomes Dias
• Grantee: Larissa Menezes dos Reis
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated research grant: 09/10875-9 - Cellular and biochemical studies of the glutaminase enzyme and its relation with cancer, AP.JP

Abstract

The Triple-negative breast cancer is characterized by the absence of progesterone and estrogen hormone receptors and HER2 membrane receptor, therefore, is unresponsive to conventional treatment of disease. Among others, changes in the cellular metabolism are the molecular basis for the emergence and progression of triple-negative, indicating that it can provide good therapeutic targets. Increase in glutamine consumption is one of the main metabolic alteration in tumor cells, and is important for the anaplerosis of the Tricarboxylic Acid Cycle (TCA), since it replaces intermediates of this cycle used on bio synthetics routes. BPTES is a potent inhibitor of glutamine metabolism, although studies in our laboratory have shown that the sensitivity of cancer cells to this compound varies, suggesting compensatory mechanisms for the glutamine anaplerosis blockage. The present work aims at the identification of alternative anaplerotic mechanisms in breast cancer cells less sensitive to BPTES, emphasizing on triple-negative breast cancer`s type of tumor. In parallel, we will also evaluate new metabolic targets on those cells. As a strategy, cell lines with low sensitivity to the compound will be subjected to gene knock down of metabolic enzymes, using a library of siRNA, in the presence of BPTES. The impact of this blockage in cancer cells survival will be measured by cell proliferation, quantification of mitochondrial mass and apoptosis assays.