title: Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα- breast cancer.
abstract: Human Epidermal Growth Factor Receptor 2-positive (HER2(+)) breast cancer (BC) is a highly aggressive disease commonly treated with chemotherapy and anti-HER2 drugs, including trastuzumab. There is currently no way to predict which HER2(+) BC patients will benefit from these treatments. Previous prognostic signatures for HER2(+) BC were developed irrespective of the subtype or the hierarchical organization of cancer in which only a fraction of cells, tumor-initiating cells (TICs), can sustain tumor growth. Here, we used serial dilution and single-cell transplantation assays to identify MMTV-Her2/Neu mouse mammary TICs as CD24(+):JAG1(-) at a frequency of 2-4.5%. A 17-gene Her2-TIC-enriched signature (HTICS), generated on the basis of differentially expressed genes in TIC versus non-TIC fractions and trained on one HER2(+) BC cohort, predicted clinical outcome on multiple independent HER2(+) cohorts. HTICS included up-regulated genes involved in S/G2/M transition and down-regulated genes involved in immune response. Its prognostic power was independent of other predictors, stratified lymph node(+) HER2(+) BC into low and high-risk subgroups, and was specific for HER2(+):estrogen receptor alpha-negative (ERα(-)) patients (10-y overall survival of 83.6% for HTICS(-) and 24.0% for HTICS(+) tumors; hazard ratio = 5.57; P = 0.002). Whereas HTICS was specific to HER2(+):ERα(-) tumors, a previously reported stroma-derived signature was predictive for HER2(+):ERα(+) BC. Retrospective analyses revealed that patients with HTICS(+) HER2(+):ERα(-) tumors resisted chemotherapy but responded to chemotherapy plus trastuzumab. HTICS is, therefore, a powerful prognostic signature for HER2(+):ERα(-) BC that can be used to identify high risk patients that would benefit from anti-HER2 therapy.
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Research Institute,  University Health Network, Toronto, ON,  Canada M5G 2M9.
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Liu
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.forename: Tao
authors.initials: T
authors.lastname: Deng
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: William Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051927:CD24 Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020360:Neoadjuvant Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051927:CD24 Antigen; D002135:Calcium-Binding Proteins; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000072099:Serrate-Jagged Proteins; D000068878:Trastuzumab; C506487:ESR1 protein, human; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse