Oral Presentation Australasian RNA Biology and Biotechnology Association 2025 Conference

Development of a potential lncRNA therapeutic for ER+ breast cancer (127452)

Haran Sivakumaran 1 , Sneha Nair 1 , Maina Bitar 1 2 , Xue Lu 1 2 , Lu Wang 1 2 , Quan H Nguyen 1 3 , Jonathan Beesley 1 , Michelle Wykes 1 , Juliet D French 1 2 , Stacey L Edwards 1 2
  1. Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  2. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

Interferons (IFNs) play a central role in controlling cell growth and activating anti-tumour immune responses. Through targeted RNA sequencing and CRISPR-Cas13d screening, we identified a previously uncharacterised, risk-associated long noncoding RNA (lncRNA) called BRRIAR, that boosts IFN pathway activity in estrogen receptor-positive (ER+) breast cancer. BRRIAR is transcribed from an 11 kb super-enhancer on chromosome 3p26 and is predominantly expressed in ER+ breast tumours. Functional studies revealed that BRRIAR acts both in cis and in trans. In the nucleus, BRRIAR facilitates chromatin looping to regulate BHLHE40 expression, a transcription factor involved in cytokine regulation. In the cytoplasm, BRRIAR binds RIG-I, a pattern recognition receptor critical for innate immune sensing. Rather than directly activating RIG-I, BRRIAR primes the receptor, enhancing its responsiveness to classical RIG-I ligands and promoting pro-inflammatory cytokine production. When delivered as an in vitro transcribed (IVT) RNA, BRRIAR rapidly induced dose-dependent apoptosis specifically in ER+ breast cancer cells and activated immune responses in human peripheral blood mononuclear cells. In vivo, lipid nanoparticle delivery of IVT BRRIAR triggered tumour-intrinsic IFN production, suppressed tumour growth, and extended survival in mouse models. Strikingly, IVT BRRIAR-mediated cell death was restricted to ER+ breast tumours that endogenously express BRRIAR, highlighting its dual potential as a predictive biomarker and a tumour-selective RNA therapeutic. Together, these findings reveal a novel link between genetic risk, lncRNA function, cancer immunosurveillance and breast tumourigenesis, establishing BRRIAR as a promising lncRNA-based therapeutic candidate for ER+ breast cancer.