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.

Authors	Milevskiy, Michael J. G.; Al-Ejeh, Fares; Saunus, Jodi M.; Northwood, Korinne S.; Bailey, Peter J.; Betts, Joshua A.; Reed, Amy E. McCart; 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.
Journal	HUMAN MOLECULAR GENETICS
Pages	3269-3283
Volume	25
Date	1/08/2016
Grant ID	NBCF: 2007003445
Funding Body	National Breast Cancer Foundation of Australia
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1093/hmg/ddw177