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. and Brown, Melissa A. (2016) Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. Human Molecular Genetics, . doi:10.1093/hmg/ddw177


Author 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.
Title Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer
Formatted title
Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 1460-2083
0964-6906
Publication date 2016-07-04
Sub-type Article (original research)
DOI 10.1093/hmg/ddw177
Open Access Status DOI
Total pages 40
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2017
Language eng
Formatted abstract
Predicting response to endocrine therapy and survival in estrogen 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 estrogen, positively regulated by FOXA1 and FOXM1, and is inversely correlated with estrogen receptor and directly correlated with FOXM1 in breast tumors. The combination of HOTAIR and FOXM1 enables greater discrimination of endocrine therapy responders and non-responders in patients with estrogen 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 tumors, and these factors enhance the prognostic power of HOTAIR in aggressive HER2+ breast tumors. 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.
Keyword Breast cancer
Endocrine therapy
HOTAIR
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Fri, 15 Jul 2016, 11:49:38 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences