Transcriptomics and metabolomics of triple negative breast tumor reveal their metabolic adaptation

Author(s)

Melissa Quintero Escobar

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2016-11-22

Examining board members

Sandra Martha Gomes Dias; Juliana Helena Costa Smetana; Katlin Brauer Massirer; Mariana Maschietto; Daniela Barretto Barbosa Trivella

• Advisor: Sandra Martha Gomes Dias; Ana Carolina de Mattos Zeri

Abstract

Great advances have been made over the years in our understanding of cancer, but many details of the mechanisms involved for tumor development are not yet fully understood. Recently, the ability to reprogram the energy metabolism was recognized as one of the hallmarks of tumoral transformation. His study and understanding has opened promising new doors in the search for therapeutic targets. About 10-20% of cases of breast cancer diagnosed corresponds to triple negative (TN) subtype, which does not express the hormones receptors of estrogen and progesterone and does not have HER2 amplification. TN tumors have a unique molecular profile, an aggressive behavior and a poor prognosis compared to others breast cancer subtypes. In addition, TN tumors do not respond to conventional treatments developed for the disease, which highlights the need to look for new therapeutic strategies. TN tumors increase the uptake of 2-deoxy-2- (18F) fluoro-D-glucose (FDG) and has a glutamine dependence, which correlates with their high proliferative index and demonstrates the enhancement of aerobic glycolysis or Warburg effect. In this study, we aimed to analyze differential gene expression and metabolomics from cell lines and tumor breast tissues TN and not TN (N-TN) subtypes in order to characterize the metabolic signature. Finally, we aimed to identify potential therapeutic targets for treatment of this tumor subtype (TN). As a result, we found that TN tumors potentially have characteristics that guarantee them a high efficiency in the use of nutrients, with high uptake and processing of glucose, high glutamine processing, re-use lactate and use of acetaldehyde as energy and biosynthetic source. This last resource could be an important way of chemoresistance. There is also activation of synthesis and modification pathways of lipids that can have important signaling function in cells. Finally, we generated a list of 73 genes with increased expression in TN breast tumors (relative to non-TN) and from this list, GBP1 a guanylate-binding protein, shown to reduce selectively the cell proliferation in TN cell lines when muted. Its function for the establishment / progression / survival TN subtype must be evaluated to confirm it or not as a potential target to treat this disease (AU)

• FAPESP's process: 12/09452-9 - Transcriptome and metabolomic studies of cancer cells as a tool for understanding the metabolic adaptation process
• Grantee: Melissa Quintero Escobar
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)