title: Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) is an aggressive subtype defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Expression of miR-21, an oncomiR, is frequently altered and may be distinctly expressed in the tumor stroma. Because tumor lesions are a complex mixture of cell types, we hypothesized that analysis of miR-21 expression at single-cell resolution could provide more accurate information to assess disease recurrence risk and BC-related death. We implemented a fully automated, tissue slide-based assay to detect miR-21 expression in 988 patients with BC. The miR-21(High) group exhibited shorter recurrence-free survival [hazard ratio (HR), 1.71; P < 0.001] and BC-specific survival (HR, 1.96; P < 0.001) in multivariate regression analyses. When tumor compartment and levels of miR-21 expression were considered, significant associations with poor clinical outcome were detected exclusively in tumor epithelia from estrogen receptor- and/or progesterone receptor-positive human epidermal growth factor receptor 2-negative cases [recurrence-free survival: HR, 3.67 (P = 0.006); BC-specific survival: HR, 5.13 (P = 0.002)] and in tumor stroma from TNBC cases [recurrence-free survival: HR, 2.59 (P = 0.013); BC-specific survival: HR, 3.37 (P = 0.003)]. These findings suggest that the context of altered miR-21 expression provides clinically relevant information. Importantly, miR-21 expression was predominantly up-regulated and potentially prognostic in the tumor stroma of TNBC.
authors.affiliation: Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Todd A
authors.initials: TA
authors.lastname: MacKenzie
authors.affiliation: Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Gary N
authors.initials: GN
authors.lastname: Schwartz
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Calderone
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Graveel
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Winn
authors.affiliation: Laboratory of Analytical Pathology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Wells
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan; Laboratory of microRNA Diagnostics and Therapeutics, Van Andel Research Institute, Grand Rapids, Michigan. Electronic address: lorenzo.sempere@vai.org.
authors.forename: Lorenzo F
authors.initials: LF
authors.lastname: Sempere
mesh_terms: D000368:Aged; D002470:Cell Survival; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D018719:Erb-b2 Receptor Tyrosine Kinases; C524940:MIRN21 microRNA, human; C508053:ERBB2 protein, human