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.
Highlights
MicroRNAs are short 18–24 nucleotide RNAs that work as post-transcriptional regulators by binding to sequences in the 39 untranslated region (39 UTR) of target mRNAs either through fully complementary or imperfect base-pairing, usually resulting in mRNA silencing [1,2]
The expression of miR-34a was investigated in an extensive series of breast tumours – altogether, samples from 1172 tumours were scored for miR-34a
Multivariate analysis, adjusting for the conventional adverse prognostic factors to evaluate the independent effect of miR-34a expression on breast cancer survival, indicated that miR-34a expression was associated with a lower risk of recurrence or death from breast cancer
Summary
MicroRNAs (miRs) are short 18–24 nucleotide RNAs that work as post-transcriptional regulators by binding to sequences in the 39 untranslated region (39 UTR) of target mRNAs either through fully complementary or imperfect base-pairing, usually resulting in mRNA silencing [1,2]. The miR-34 family has become a promising topic in cancer research [6]. This miR family consists of three members, namely miR-34a, miR-34b and miR-34c, which are encoded by two different genes: miR-34a is transcribed from its own independent locus, whereas miR-34b and miR-34c share a common primary transcript. MiR-34a resides on the chromosomal locus 1p36.23, and the loss of this region is associated with a variety of cancer types [7]. MiR-34a is highly expressed in normal tissues, like testis, lung, adrenal gland and spleen, where its physiological
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