title: A computational strategy to select optimized protein targets for drug development toward the control of cancer diseases.
abstract: In this report, we describe a strategy for the optimized selection of protein targets suitable for drug development against neoplastic diseases taking the particular case of breast cancer as an example. We combined human interactome and transcriptome data from malignant and control cell lines because highly connected proteins that are up-regulated in malignant cell lines are expected to be suitable protein targets for chemotherapy with a lower rate of undesirable side effects. We normalized transcriptome data and applied a statistic treatment to objectively extract the sub-networks of down- and up-regulated genes whose proteins effectively interact. We chose the most connected ones that act as protein hubs, most being in the signaling network. We show that the protein targets effectively identified by the combination of protein connectivity and differential expression are known as suitable targets for the successful chemotherapy of breast cancer. Interestingly, we found additional proteins, not generally targeted by drug treatments, which might justify the extension of existing formulation by addition of inhibitors designed against these proteins with the consequence of improving therapeutic outcomes. The molecular alterations observed in breast cancer cell lines represent either driver events and/or driver pathways that are necessary for breast cancer development or progression. However, it is clear that signaling mechanisms of the luminal A, B and triple negative subtypes are different. Furthermore, the up- and down-regulated networks predicted subtype-specific drug targets and possible compensation circuits between up- and down-regulated genes. We believe these results may have significant clinical implications in the personalized treatment of cancer patients allowing an objective approach to the recycling of the arsenal of available drugs to the specific case of each breast cancer given their distinct qualitative and quantitative molecular traits.
authors.affiliation: Laboratório de Modelagem de Sistemas Biológicos, National Institute of Science and Technology for Innovation in Neglected Diseases (INCT/IDN, CNPq), Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Carels
authors.affiliation: Laboratório de Modelagem de Sistemas Biológicos, National Institute of Science and Technology for Innovation in Neglected Diseases (INCT/IDN, CNPq), Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tilli
authors.affiliation: Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2; Department of Physics, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents