title: MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer.
abstract: MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and γH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41-0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5-year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co-operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer.
authors.affiliation: Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Peurala
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Sippy
authors.initials: S
authors.lastname: Kaur
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Maral
authors.initials: M
authors.lastname: Jamshidi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D018275:Carcinoma, Lobular / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D019927:Cyclin E / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006657:Histones / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015996:Survival Rate; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; D004268:DNA-Binding Proteins; D006657:Histones; D035683:MicroRNAs; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C468783:H2AX protein, human; C522425:MIRN34 microRNA, human; C495901:TP53 protein, human; C076035:c-MYC-associated zinc finger protein; C508053:ERBB2 protein, human
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