title: Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status.
abstract: The tumor suppressor p53 is the most frequently mutated gene in human cancers, mutated in 25-30% of breast cancers. However, mutation rates differ according to breast cancer subtype, being more prevalent in aggressive estrogen receptor-negative tumors and basal-like and HER2-amplified subtypes. This heterogeneity suggests that p53 may function differently across breast cancer subtypes. We used RNAi-mediated p53 knockdown (KD) and antagomir-mediated KD of microRNAs to study how gene expression and cellular response to p53 loss differ in luminal versus basal-like breast cancer. As expected, p53 loss caused downregulation of established p53 targets (e.g. p21 and miR-34 family) and increased proliferation in both luminal and basal-like cell lines. However, some p53-dependent changes were subtype specific, including expression of miR-134, miR-146a and miR-181b. To study the cellular response to miR-146a upregulation in p53-impaired basal-like lines, antagomir KD of miR-146a was performed. KD of miR-146a caused decreased proliferation and increased apoptosis, effectively ablating the effects of p53 loss. Furthermore, we found that miR-146a upregulation decreased NF-κB expression and downregulated the NF-κB-dependent extrinsic apoptotic pathway (including tumor necrosis factor, FADD and TRADD) and antagomir-mediated miR-146a KD restored expression of these components, suggesting a plausible mechanism for miR-146a-dependent cellular responses. These findings are relevant to human basal-like tumor progression in vivo, since miR-146a is highly expressed in p53 mutant basal-like breast cancers. These findings suggest that targeting miR-146a expression may have value for altering the aggressiveness of p53 mutant basal-like tumors.
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA.
authors.forename: Rupninder
authors.initials: R
authors.lastname: Sandhu
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Rein
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: D'Arcy
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA and.
authors.forename: Jason I
authors.initials: JI
authors.lastname: Herschkowitz
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA troester@unc.edu.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53