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 ?H2AX (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.

SUBMITTER: Peurala H 

PROVIDER: S-EPMC3213093 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature