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

Milevskiy, Michael J.G., Al-Ejeh, Fares, Saunus, Jodi M., Northwood, Korinne S., Bailey, Peter J., Betts, Joshua A., McCart Reed, Amy E., Nephew, Kenneth P., Stone, Andrew, Gee, Julia M.W., Dowhan, Dennis H., Dray, Eloise, Shewan, Annette M., French, Juliet D., Edwards, Stacey L., Clark, Susan J., Lakhani, Sunil R., & Brown, Melissa A. (2016) Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. Human Molecular Genetics. (In Press)

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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.

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ID Code: 98796
Item Type: Journal Article
Refereed: Yes
Keywords: breast cancer, biomarkers, non-coding RNA, endocrine therapy
DOI: 10.1093/hmg/ddw177
ISSN: 1460-2083
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2016 The Author
Copyright Statement: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Deposited On: 12 Sep 2016 23:46
Last Modified: 14 Sep 2016 00:01

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