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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.

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