title: Downregulation of miR-92a is associated with aggressive breast cancer features and increased tumour macrophage infiltration.
abstract: BACKGROUND
  MicroRNAs are small non-coding RNAs involved in the regulation of gene expression on a posttranscriptional level. These regulatory RNAs have been implicated in numerous cellular processes and are further deregulated in different cancer types, including breast cancer. MiR-92a is part of the miR-17∼92 cluster, which was first reported to be linked to tumourigenesis. However, little is known about the expression of miR-92a in breast cancer and potential associations to tumour properties. The expression of miR-92a was therefore characterized in 144 invasive breast cancer samples using in situ hybridization and related to clinico-pathological data as well as to selected key properties of the tumour stroma, including the presence of macrophages (CD68) and cancer activated fibroblasts (alpha-SMA).
  
  
  RESULTS
  To measure miR-92a levels, an in situ hybridisation protocol was developed and validated using cell lines and miR-92a inhibitors. The expression in the tumour samples was objectively evaluated using digital image analysis program subtracting background activities. We found that the miR-92a expression varied between tumours and was inversely correlated to tumour grade (r = -0.276, p = 0.003) and recurrence-free survival (p = 0.008) and provided independent prognostic information in multivariate Cox analysis (HR: 0.375, CI: 0.145-0.972, p = 0.043). MiR-92a was moreover inversely correlated to the number of infiltrating macrophages in the tumour stroma (r = -0.357, p<0.001), and downregulation of miR-92a promoted cell migration (p<0.01).
  
  
  CONCLUSIONS
  This study demonstrates that downregulation of miR-92a in breast cancer is linked to key epithelial and stromal properties as well as clinical outcome.
authors.affiliation: Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Sofie
authors.initials: S
authors.lastname: Nilsson
authors.forename: Christina
authors.initials: C
authors.lastname: Möller
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Alexander
authors.initials: A
authors.lastname: Lee
authors.forename: Susann
authors.initials: S
authors.lastname: Busch
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lamb
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008264:Macrophages / Q000502:physiology*; D035683:MicroRNAs / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D012984:Software
chemical_list: C541874:MIRN92 microRNA, human; D035683:MicroRNAs