Research Papers:

Molecular characterization of breast cancer cell response to metabolic drugs

Lucía Trilla-Fuertes, Angelo Gámez-Pozo, Jorge M. Arevalillo, Mariana Díaz-Almirón, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Hilario Navarro, Rosa Aras-López, Irene Dapía, Rocío López-Vacas, Paolo Nanni, Sara Llorente-Armijo, Pedro Arias, Alberto M. Borobia, Paloma Maín, Jaime Feliú, Enrique Espinosa and Juan Ángel Fresno Vara _

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Oncotarget. 2018; 9:9645-9660. https://doi.org/10.18632/oncotarget.24047

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Lucía Trilla-Fuertes1,2, Angelo Gámez-Pozo1,2, Jorge M. Arevalillo3, Mariana Díaz-Almirón4, Guillermo Prado-Vázquez1, Andrea Zapater-Moros1, Hilario Navarro3, Rosa Aras-López5, Irene Dapía6,7, Rocío López-Vacas1, Paolo Nanni8, Sara Llorente-Armijo1, Pedro Arias6,7, Alberto M. Borobia9, Paloma Maín10, Jaime Feliú11,12,13, Enrique Espinosa11,12 and Juan Ángel Fresno Vara1,2,12

1Molecular Oncology and Pathology Lab, Institute of Medical and Molecular Genetics-INGEMM, La Paz University Hospital-IdiPAZ, Madrid, Spain

2Biomedica Molecular Medicine SL, Madrid, Spain

3Operational Research and Numerical Analysis, National Distance Education University (UNED), Madrid, Spain

4Biostatistics Unit, La Paz University Hospital-IdiPAZ, Madrid, Spain

5Congenital Malformations Lab, Institute of Medical and Molecular Genetics-INGEMM, La Paz University Hospital, IdiPAZ, Madrid, Spain

6Pharmacogenetics Lab, Institute of Medical and Molecular Genetics-INGEMM, La Paz University Hospital-IdiPAZ, Autonomous University of Madrid, Madrid, Spain

7Biomedical Research Networking Center on Rare Diseases-CIBERER, ISCIII, Madrid, Spain

8Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Zurich, Switzerland

9Clinical Pharmacology Department, La Paz University Hospital School of Medicine, IdiPAZ, Autonomous University of Madrid, Madrid, Spain

10Department of Statistics and Operations Research, Faculty of Mathematics, Complutense University of Madrid, Madrid, Spain

11Medical Oncology Service, La Paz University Hospital-IdiPAZ, Madrid, Spain

12Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain

13Cátedra UAM-AMGEN, Universidad Autónoma de Madrid, Madrid, Spain

Correspondence to:

Juan Ángel Fresno Vara, email: [email protected]

Keywords: breast cancer; flux balance analysis; metabolism; perturbation experiments; proteomics

Received: October 29, 2017     Accepted: January 03, 2018     Published: January 08, 2018


Metabolic reprogramming is a hallmark of cancer. It has been described that breast cancer subtypes present metabolism differences and this fact enables the possibility of using metabolic inhibitors as targeted drugs in specific scenarios. In this study, breast cancer cell lines were treated with metformin and rapamycin, showing a heterogeneous response to treatment and leading to cell cycle disruption. The genetic causes and molecular effects of this differential response were characterized by means of SNP genotyping and mass spectrometry-based proteomics. Protein expression was analyzed using probabilistic graphical models, showing that treatments elicit various responses in some biological processes such as transcription. Moreover, flux balance analysis using protein expression values showed that predicted growth rates were comparable with cell viability measurements and suggesting an increase in reactive oxygen species response enzymes due to metformin treatment. In addition, a method to assess flux differences in whole pathways was proposed. Our results show that these diverse approaches provide complementary information and allow us to suggest hypotheses about the response to drugs that target metabolism and their mechanisms of action.

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