title: Chromosomal instability selects gene copy-number variants encoding core regulators of proliferation in ER+ breast cancer.
abstract: Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER(+)) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER(+) breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation.
authors: Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences Koblenz, 53424 Remagen, Germany.|Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Biomathematics and Biometry, Scientific Computing Research Unit, Neuherberg, Germany.
authors: David
authors: D
authors: Endesfelder
authors: Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors: Rebecca
authors: R
authors: Burrell
authors: UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6BT London.
authors: Nnennaya
authors: N
authors: Kanu
authors: Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors: Nicholas
authors: N
authors: McGranahan
authors: High Throughput Screening Laboratory,Cancer Research UK London Research Institute, London, United Kingdom.
authors: Mike
authors: M
authors: Howell
authors: Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.|Division of Cancer Studies, King's College London, London SE1 1UL.
authors: Peter J
authors: PJ
authors: Parker
authors: Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors: Julian
authors: J
authors: Downward
authors: Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.|Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors: Charles
authors: C
authors: Swanton
authors: Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences Koblenz, 53424 Remagen, Germany.
authors: Maik
authors: M
authors: Kschischo
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; C122167:TPX2 protein, human; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes