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MiR-34a expression ...
MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer
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Peurala, Hanna (author)
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Greco, Dario (author)
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Heikkinen, Tuomas (author)
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Kaur, Sippy (author)
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Bartkova, Jirina (author)
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Jamshidi, Maral (author)
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Aittomäki, Kristiina (author)
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Heikkilä, Päivi (author)
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Bartek, Jiri (author)
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- Blomqvist, Carl (author)
- Uppsala universitet,Enheten för onkologi
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Bützow, Ralf (author)
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Nevanlinna, Heli (author)
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(creator_code:org_t)
- 2011-11-10
- 2011
- English.
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11, s. e26122-
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Abstract
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- 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.
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- By the author/editor
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Peurala, Hanna
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Greco, Dario
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Heikkinen, Tuoma ...
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Kaur, Sippy
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Bartkova, Jirina
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Jamshidi, Maral
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show more...
-
Aittomäki, Krist ...
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Heikkilä, Päivi
-
Bartek, Jiri
-
Blomqvist, Carl
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Bützow, Ralf
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Nevanlinna, Heli
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show less...
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PLOS ONE
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Uppsala University