title: Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer.
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.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
authors.forename: Michael J G
authors.initials: MJ
authors.lastname: Milevskiy
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Fares
authors.initials: F
authors.lastname: Al-Ejeh
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Herston, Australia.
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Saunus
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.|The University of Queensland, UQ Centre for Clinical Research, Herston, Australia.
authors.forename: Korinne S
authors.initials: KS
authors.lastname: Northwood
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.|Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bailey
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.|QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Betts
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Herston, Australia.
authors.forename: Amy E
authors.initials: AE
authors.lastname: McCart Reed
authors.affiliation: Indiana University, School of Medicine, Bloomington, IN, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.affiliation: Epigenetics Research Laboratory, Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stone
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Dowhan
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.|Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.|Queensland University of Technology, Brisbane, Australia.
authors.forename: Eloise
authors.initials: E
authors.lastname: Dray
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Shewan
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.|QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Juliet D
authors.initials: JD
authors.lastname: French
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.|QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Edwards
authors.affiliation: Epigenetics Research Laboratory, Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Herston, Australia.|Pathology Queensland, The Royal Brisbane & Women's Hospital, Herston, Australia.|The University of Queensland School of Medicine, Herston, Australia.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia melissa.brown@uq.edu.au.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; C496499:FOXA1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C561566:HOTAIR long untranslated RNA, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm