title: Development and validation of a novel platform-independent metastasis signature in human breast cancer.
abstract: OBJECTIVE
  The molecular drivers of metastasis in breast cancer are not well understood. Therefore, we sought to identify the biological processes underlying distant progression and define a prognostic signature for metastatic potential in breast cancer.
  
  
  METHODS
  In vivo screening for metastases was performed using Chick Chorioallantoic Membrane assays in 21 preclinical breast cancer models. Expressed genes associated with metastatic potential were identified using high-throughput analysis. Correlations with biological function were determined using the Database for Annotation, Visualization and Integrated Discovery.
  
  
  RESULTS
  We identified a broad range of metastatic potential that was independent of intrinsic breast cancer subtypes. 146 genes were significantly associated with metastasis progression and were linked to cancer-related biological functions, including cell migration/adhesion, Jak-STAT, TGF-beta, and Wnt signaling. These genes were used to develop a platform-independent gene expression signature (M-Sig), which was trained and subsequently validated on 5 independent cohorts totaling nearly 1800 breast cancer patients with all p-values < 0.005 and hazard ratios ranging from approximately 2.5 to 3. On multivariate analysis accounting for standard clinicopathologic prognostic variables, M-Sig remained the strongest prognostic factor for metastatic progression, with p-values < 0.001 and hazard ratios > 2 in three different cohorts.
  
  
  CONCLUSIONS
  M-Sig is strongly prognostic for metastatic progression, and may provide clinical utility in combination with treatment prediction tools to better guide patient care. In addition, the platform-independent nature of the signature makes it an excellent research tool as it can be directly applied onto existing, and future, datasets.
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Shuang G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Shilkrut
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Corey
authors.initials: C
authors.lastname: Speers
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Kari
authors.initials: K
authors.lastname: Wilder-Romans
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pierce
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
mesh_terms: D020087:Alu Elements / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002642:Chick Embryo; D002645:Chickens / Q000254:growth & development / Q000378:metabolism; D049033:Chorioallantoic Membrane / Q000378:metabolism; D015331:Cohort Studies; D004247:DNA / Q000032:analysis / Q000302:isolation & purification; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008954:Models, Biological; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D004247:DNA