Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer

Milevskiy, M. J.G. et al. (2016) Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. Human Molecular Genetics, 25(15), pp. 3269-3283. (doi: 10.1093/hmg/ddw177) (PMID:27378691) (PMCID:PMC5179926)

Abstract

Predicting response to endocrine therapy and survival in oestrogen receptor positive breast cancer is a significant clinical challenge and novel prognostic biomarkers are needed. Long-range regulators of gene expression are emerging as promising biomarkers and therapeutic targets for human diseases, so we have explored the potential of distal enhancer elements of non-coding RNAs in the prognostication of breast cancer survival. HOTAIR is a long non-coding RNA that is overexpressed, promotes metastasis and is predictive of decreased survival. Here, we describe a long-range transcriptional enhancer of the HOTAIR gene that binds several hormone receptors and associated transcription factors, interacts with the HOTAIR promoter and augments transcription. This enhancer is dependent on Forkhead-Box transcription factors and functionally interacts with a novel alternate HOTAIR promoter. HOTAIR expression is negatively regulated by oestrogen, positively regulated by FOXA1 and FOXM1, and is inversely correlated with oestrogen receptor and directly correlated with FOXM1 in breast tumours. The combination of HOTAIR and FOXM1 enables greater discrimination of endocrine therapy responders and non-responders in patients with oestrogen receptor positive breast cancer. Consistent with this, HOTAIR expression is increased in cell-line models of endocrine resistance. Analysis of breast cancer gene expression data indicates that HOTAIR is co-expressed with FOXA1 and FOXM1 in HER2-enriched tumours, and these factors enhance the prognostic power of HOTAIR in aggressive HER2+ breast tumours. Our study elucidates the transcriptional regulation of HOTAIR, identifies HOTAIR and its regulators as novel biomarkers of patient response to endocrine therapy and corroborates the importance of transcriptional enhancers in cancer.

• Item Type: Articles
• Additional Information: Research was funded by the National Breast Cancer Foundation (NBCF: 2007003445 and CG-12-07) of Australia, the Australian Research Council (ARC: DP0985025), the Cancer Council of Queensland (CCQ: 1026095) and The University of Queensland. DHD was supported by a Collaborative Program Grant from the, National Breast Cancer Foundation [NBCF; CG-08-03]. Institute, Integrative Cancer Biology Program U54CA1113001 (KPN). SLE, JDF, AMS and ED are supported by Fellowships from the NBCF [ID# ECF-10-05, ECF-12-04, ECF-12-12 and ECF-13-04 respectively]. FA is supported by Future Fellowship from the Australian Research Council [ID: FT130101417]. JMWG is funding by a Scientific Fellowship from Breast Cancer Now. MJM and JAB are supported by an Australian Postgraduate Award (APA). AS was supported from NBCF program grant. SJC supported by NHMRC fellowship. Funding to pay the Open Access publication charges for this article was provided by The University of Queensland.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bailey, Dr Peter
• Authors: Milevskiy, M. J.G., Al-Ejeh, F., Saunus, J. M., Northwood, K. S., Bailey, P. J., Betts, J. A., McCart Reed, A. E., Nephew, K. P., Stone, A., Gee, J. M.W., Dowhan, D. H., Dray, E., Shewan, A. M., French, J. D., Edwards, S. L., Clark, S. J., Lakhani, S. R., and Brown, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Human Molecular Genetics
• Publisher: Oxford University Press
• ISSN: 0964-6906
• ISSN (Online): 1460-2083
• Published Online: 04 July 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Human Molecular Genetics 25(15):3269-3283
• Publisher Policy: Reproduced under a Creative Commons License