Poster Presentation & Flash Talk Presentation 28th Lorne Cancer Conference 2016

Long-range regulation of HOTAIR identifies novel biomarkers of breast cancer outcome and suggests a role in genome instability (#210)

Michael J.G. Milevskiy 1 , Fares Al-Ejeh 2 , Jodi Saunus 3 , Korinne Northwood 1 3 , Peter Bailey 4 , Joshua Betts 2 , Amy McCart Reed 3 , Kenneth Nephew 5 , Andrew Stone 6 7 , Julia Gee 8 , Dennis Dowhan 9 , Eloise Dray 10 , Annette Shewan 1 , Juliet French 2 , Stacey Edwards 2 , Susan Clark 6 7 , Sunil Lakhani 3 9 11 , Melissa Brown 1
  1. The School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia
  2. Berghofer Medical Research Institute, Queensland Institute of Medical Research, Brisbane, QLD, Australia
  3. UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia
  4. Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom
  5. School of Medicine, Indiana University, Bloomington, IN, USA
  6. Epigenetics Research Program, Cancer Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  7. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  8. School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, United Kingdom
  9. Institute of Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
  10. Institute of Health and Biomedical Innovation, Translational Research Insitute, Brisbane, QLD, Australia
  11. School of Medicine, The University of Queensland, Herston, QLD, Australia

Long-range regulators of gene expression are emerging as promising new biomarkers and therapeutic targets for human diseases including cancer. As current breast cancer biomarkers have limited power for predicting disease progression and response to therapy, we have explored the potential of long-range regulators of non-coding RNAs to be useful in the prognostication of breast cancer. HOTAIR is a long non-coding RNA that is overexpressed, promotes metastasis, and is predictive of poor prognosis in breast cancer. 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 HOTAIR transcription. This enhancer is dependent on FOXA1 and FOXM1 transcription factors and functionally interacts with a novel alternate HOTAIR promoter. 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 more aggressive breast tumours of this subtype. The combination of HOTAIR and FOXM1 also enables better predictions of response to endocrine therapy for ER+ breast cancer. FOXM1 is a member of the recently described chromosome instability module and consistent with this, the expression of HOTAIR and FOXM1 is associated with increased frequency of copy number alterations and somatic non-synonymous mutations. Our study corroborates the importance of enhancers in breast cancer, elucidates the transcriptional regulation of HOTAIR, suggests HOTAIR as a novel biomarker of patient response to endocrine therapy, and implicates HOTAIR in chromosome instability.