title: Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.
abstract: Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan; Stem Cell Therapy Center, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan.
authors.forename: Elham Abu
authors.initials: EA
authors.lastname: Sharieh
authors.affiliation: Stem Cell Therapy Center, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan; Department of Internal Medicine Hematology and Oncology Unit, University of Jordan, Amman 11942, Jordan.
authors.forename: Abdulla S
authors.initials: AS
authors.lastname: Awidi
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan.
authors.forename: Mamoun
authors.initials: M
authors.lastname: Ahram
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan. Electronic address: m.zihlif@ju.edu.jo.
authors.forename: Malek A
authors.initials: MA
authors.lastname: Zihlif
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D000068878:Trastuzumab
keywords: Epithelial-to mesenchymal transition; Trastuzumab resistance