title: The Tyrosine Kinome Dictates Breast Cancer Heterogeneity and Therapeutic Responsiveness.
abstract: Phospho-tyrosine signaling networks control numerous biological processes including cellular differentiation, cell growth and survival, motility, and invasion. Aberrant regulation of the tyrosine kinome is a hallmark of malignancy and influences all stages of breast cancer progression, from initiation to the development of metastatic disease. The success of specific tyrosine kinase inhibitors strongly validates the clinical relevance of tyrosine phosphorylation networks in breast cancer pathology. However, a significant degree of redundancy exists within the tyrosine kinome. Numerous receptor and cytoplasmic tyrosine kinases converge on a core set of signaling regulators, including adaptor proteins and tyrosine phosphatases, to amplify pro-tumorigenic signal transduction pathways. Mutational activation, amplification, or overexpression of one or more components of the tyrosine kinome represents key contributing events responsible for the tumor heterogeneity that is observed in breast cancers. It is this molecular heterogeneity that has become the most significant barrier to durable clinical responses due to the development of therapeutic resistance. This review focuses on recent literature that supports a prominent role for specific components of the tyrosine kinome in the emergence of unique breast cancer subtypes and in shaping breast cancer plasticity, sensitivity to targeted therapies, and the eventual emergence of acquired resistance. J. Cell. Biochem. 117: 1971-1990, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.|Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Ha
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.|Department of Oncology, McGill University, Montreal, Quebec, Canada.|Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.|Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Josie
authors.initials: J
authors.lastname: Ursini-Siegel
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D010749:Phosphoprotein Phosphatases
keywords: ADAPTOR PROTEINS; BREAST CANCER SUBTYPE; SIGNAL TRANSDUCTION; THERAPEUTIC RESISTANCE; TYROSINE KINASES; TYROSINE PHOSPHATASES