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

Michael J G Milevskiy, Fares Al-Ejeh, Jodi M. Saunus, Korinne S. Northwood, Peter J. Bailey, Joshua A. Betts, Amy E Mc Cart Reed, Kenneth Nephew, Andrew Stone, Julia M W Gee, Dennis H. Dowhan, Eloise Dray, Annette M. Shewan, Juliet D. French, Stacey L. Edwards, Susan J. Clark, Sunil R. Lakhani, Melissa A. Brown

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3269-3283
Number of pages15
JournalHuman Molecular Genetics
Volume25
Issue number15
DOIs
StatePublished - 2015

Fingerprint

Long Noncoding RNA
Breast Neoplasms
Estrogen Receptors
Biomarkers
Survival
Forkhead Transcription Factors
Gene Expression
Untranslated RNA
Neoplasm Genes
Therapeutics
Regulator Genes
Neoplasms
Estrogens
Transcription Factors
Hormones
Neoplasm Metastasis
Cell Line
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Milevskiy, M. J. G., Al-Ejeh, F., Saunus, J. M., Northwood, K. S., Bailey, P. J., Betts, J. A., ... Brown, M. A. (2015). Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. Human Molecular Genetics, 25(15), 3269-3283. https://doi.org/10.1093/hmg/ddw177

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.; Reed, Amy E Mc Cart; Nephew, Kenneth; 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.

In: Human Molecular Genetics, Vol. 25, No. 15, 2015, p. 3269-3283.

Research output: Contribution to journalArticle

Milevskiy, MJG, Al-Ejeh, F, Saunus, JM, Northwood, KS, Bailey, PJ, Betts, JA, Reed, AEMC, Nephew, K, Stone, A, Gee, JMW, Dowhan, DH, Dray, E, Shewan, AM, French, JD, Edwards, SL, Clark, SJ, Lakhani, SR & Brown, MA 2015, 'Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer', Human Molecular Genetics, vol. 25, no. 15, pp. 3269-3283. https://doi.org/10.1093/hmg/ddw177
Milevskiy MJG, Al-Ejeh F, Saunus JM, Northwood KS, Bailey PJ, Betts JA et al. Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. Human Molecular Genetics. 2015;25(15):3269-3283. https://doi.org/10.1093/hmg/ddw177
Milevskiy, Michael J G ; Al-Ejeh, Fares ; Saunus, Jodi M. ; Northwood, Korinne S. ; Bailey, Peter J. ; Betts, Joshua A. ; Reed, Amy E Mc Cart ; Nephew, Kenneth ; 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. / Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer. In: Human Molecular Genetics. 2015 ; Vol. 25, No. 15. pp. 3269-3283.
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AU - Al-Ejeh, Fares

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AU - Northwood, Korinne S.

AU - Bailey, Peter J.

AU - Betts, Joshua A.

AU - Reed, Amy E Mc Cart

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AU - Stone, Andrew

AU - Gee, Julia M W

AU - Dowhan, Dennis H.

AU - Dray, Eloise

AU - Shewan, Annette M.

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AB - 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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