title: Validation of a network-based strategy for the optimization of combinatorial target selection in breast cancer therapy: siRNA knockdown of network targets in MDA-MB-231 cells as an in vitro model for inhibition of tumor development.
abstract: Network-based strategies provided by systems biology are attractive tools for cancer therapy. Modulation of cancer networks by anticancer drugs may alter the response of malignant cells and/or drive network re-organization into the inhibition of cancer progression. Previously, using systems biology approach and cancer signaling networks, we identified top-5 highly expressed and connected proteins (HSP90AB1, CSNK2B, TK1, YWHAB and VIM) in the invasive MDA-MB-231 breast cancer cell line. Here, we have knocked down the expression of these proteins, individually or together using siRNAs. The transfected cell lines were assessed for in vitro cell growth, colony formation, migration and invasion relative to control transfected MDA-MB-231, the non-invasive MCF-7 breast carcinoma cell line and the non-tumoral mammary epithelial cell line MCF-10A. The knockdown of the top-5 upregulated connectivity hubs successfully inhibited the in vitro proliferation, colony formation, anchorage independence, migration and invasion in MDA-MB-231 cells; with minimal effects in the control transfected MDA-MB-231 cells or MCF-7 and MCF-10A cells. The in vitro validation of bioinformatics predictions regarding optimized multi-target selection for therapy suggests that protein expression levels together with protein-protein interaction network analysis may provide an optimized combinatorial target selection for a highly effective anti-metastatic precision therapy in triple-negative breast cancer. This approach increases the ability to identify not only druggable hubs as essential targets for cancer survival, but also interactions most susceptible to synergistic drug action. The data provided in this report constitute a preliminary step toward the personalized clinical application of our strategy to optimize the therapeutic use of anti-cancer drugs.
authors.affiliation: Laboratory of Biological System Modeling, National Institute for Science and Technology on Innovation in Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Tilli
authors.affiliation: Laboratory of Biological System Modeling, National Institute for Science and Technology on Innovation in Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Carels
authors.affiliation: Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.|Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.affiliation: Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Manijeh
authors.initials: M
authors.lastname: Pasdar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering
keywords: cancer therapy; network-based strategy; siRNA therapy; triple-negative breast cancer (TNBC)