title: MicroRNA expression as risk biomarker of breast cancer metastasis: a pilot retrospective case-cohort study.
abstract: BACKGROUND
  MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in post-transcriptional gene regulation and have recently been shown to play a role in cancer metastasis. In solid tumors, especially breast cancer, alterations in miRNA expression contribute to cancer pathogenesis, including metastasis. Considering the emerging role of miRNAs in metastasis, the identification of predictive markers is necessary to further the understanding of stage-specific breast cancer development. This is a retrospective analysis that aimed to identify molecular biomarkers related to distant breast cancer metastasis development.
  
  
  METHODS
  A retrospective case cohort study was performed in 64 breast cancer patients treated during the period from 1998-2001. The case group (n = 29) consisted of patients with a poor prognosis who presented with breast cancer recurrence or metastasis during follow up. The control group (n = 35) consisted of patients with a good prognosis who did not develop breast cancer recurrence or metastasis. These patient groups were stratified according to TNM clinical stage (CS) I, II and III, and the main clinical features of the patients were homogeneous. MicroRNA profiling was performed and biomarkers related to metastatic were identified independent of clinical stage. Finally, a hazard risk analysis of these biomarkers was performed to evaluate their relation to metastatic potential.
  
  
  RESULTS
  MiRNA expression profiling identified several miRNAs that were both specific and shared across all clinical stages (p ≤ 0.05). Among these, we identified miRNAs previously associated with cell motility (let-7 family) and distant metastasis (hsa-miR-21). In addition, hsa-miR-494 and hsa-miR-21 were deregulated in metastatic cases of CSI and CSII. Furthermore, metastatic miRNAs shared across all clinical stages did not present high sensitivity and specificity when compared to specific-CS miRNAs. Between them, hsa-miR-183 was the most significative of CSII, which miRNAs combination for CSII (hsa-miR-494, hsa-miR-183 and hsa-miR-21) was significant and were a more effective risk marker compared to the single miRNAs.
  
  
  CONCLUSIONS
  Women with metastatic breast cancer, especially CSII, presented up-regulated levels of miR-183, miR-494 and miR-21, which were associated with a poor prognosis. These miRNAs therefore represent new risk biomarkers of breast cancer metastasis and may be useful for future targeted therapies.
authors.forename: Augusto L F
authors.initials: AL
authors.lastname: Marino
authors.forename: Adriane F
authors.initials: AF
authors.lastname: Evangelista
authors.forename: René A C
authors.initials: RA
authors.lastname: Vieira
authors.forename: Taciane
authors.initials: T
authors.lastname: Macedo
authors.forename: Ligia M
authors.initials: LM
authors.lastname: Kerr
authors.forename: Lucas Faria
authors.initials: LF
authors.lastname: Abrahão-Machado
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto-Filho
authors.forename: Henrique C S
authors.initials: HC
authors.lastname: Silveira
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil. mmcmsilveira@gmail.com.
authors.forename: Marcia M C
authors.initials: MM
authors.lastname: Marques
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; C533449:MIRN183 microRNA, human; C524940:MIRN21 microRNA, human; C547168:MIRN494 microRNA, human; D035683:MicroRNAs