Predicting response to endocrine therapy and survival in estrogen 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 researchers at the University of Queensland 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 the researchers 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 estrogen, positively regulated by FOXA1 and FOXM1, and is inversely correlated with estrogen receptor and directly correlated with FOXM1 in breast tumors. The combination of HOTAIR and FOXM1 enables greater discrimination of endocrine therapy responders and non-responders in patients with estrogen 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 tumors, and these factors enhance the prognostic power of HOTAIR in aggressive HER2+ breast tumors.
Identification of a HOXC putative cis-regulatory element
by investigating chromatin modifications and long-range interactions
(A) Histone modification and transcription factor binding across the HOXC locus, sourced from publically available ChIP-Seq data (Hg18), suggesting a putative enhancer ~150 kb downstream of the HOTAIR gene. (B) ChIA-PET interactions for ESR1, RNA Polymerase II and CTCF with data sourced from GEO, GSE39495. Plots representing each interaction library include a wiggle track showing the binding of each transcription factor and a curved line that connects interacting genomic fragments indicating relative interaction frequency between fragments (right Y axis).
This 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.