BRRIAR lncRNA alters breast cancer risk by modulating interferon signaling in cis and in trans

Sivakumaran, H; Nair, S; Bitar, M; Lu, X; Wang, L; Liu, J; Karunarathne, DS; Prakrithi, P; Jacquelin, S; Rivera, IS; Hillman, KM; Kaufmann, S; Ziegman, R; Shi, W; Alexandrou, S; Caldon, CE; Veedu, RN; Nguyen, QH; Beesley, J; Wykes, MN; French, JD; Edwards, SL

Author(s): Sivakumaran, H; Nair, S; Bitar, M; Lu, X; Wang, L; Liu, J; Karunarathne, DS; Prakrithi, P; Jacquelin, S; Rivera, IS; Hillman, KM; Kaufmann, S; Ziegman, R; Shi, W; Alexandrou, S; Caldon, CE; Veedu, RN; Nguyen, QH; Beesley, J; Wykes, MN; French, JD; Edwards, SL;
Details: Publication Year 2026-01-07,Volume 25,Issue #1,Page 5
Journal Title: Molecular Cancer
Abstract: BACKGROUND: Interferons (IFNs) are key cytokines that drive immune responses against infections and cancer, yet few therapies have successfully leveraged IFN signaling for cancer treatment. Long noncoding RNAs (lncRNAs) are emerging as promising therapeutic candidates, but their roles in immune modulation remain largely unexplored. Here, we functionally characterize a breast cancer-associated lncRNA, BRRIAR, which primes the IFN signaling pathway in specific cancer contexts and represents a potential therapeutic strategy for estrogen receptor-positive (ER+) breast cancer. METHODS: BRRIAR expression and subcellular localization were examined using qPCR, in situ hybridization, single-cell RNA sequencing and spatial transcriptomics. BRRIAR target genes were identified through CRISPR interference, chromatin interaction assays and ChIP sequencing. Mechanistic studies in ER + breast cancer cells included CRISPR-Cas9 genome-wide screens, RNA sequencing, RNA pull-down followed by mass spectrometry, proliferation assays and Western blotting. The therapeutic potential of BRRIAR was evaluated via intratumoral delivery of lipid nanoparticle-encapsulated BRRIAR in ER + breast cancer xenograft models. Immune activation was assessed using flow cytometry and cytokine profiling of human peripheral blood mononuclear cells (PBMCs). RESULTS: We demonstrate that BRRIAR is a key target gene at the 3p26 breast cancer risk region. Primarily expressed in ER + breast tumors, BRRIAR acts both in cis and in trans. Nuclear BRRIAR regulates BHLHE40 expression in cis through chromatin interactions, while cytoplasmic BRRIAR binds in trans to the pattern recognition receptor RIG-I, priming IFN signaling. Overexpression of BRRIAR RNA triggers RIG-I signaling, inducing IFN responses, drives rapid, dose-dependent apoptosis of ER + breast cancer cells in vitro and in vivo, and promotes immune activation in human PBMCs. CONCLUSIONS: These findings establish lncRNAs as key regulators of tumor immunity and uncover a critical link between genetic risk, lncRNAs, cancer immunosurveillance and breast cancer development, positioning BRRIAR as a promising lncRNA-based RIG-I activator for ER + breast cancer therapy.
Publisher: Springer
Keywords: Humans; *Breast Neoplasms/genetics/metabolism/pathology/etiology; Female; *RNA, Long Noncoding/genetics; *Signal Transduction; Animals; Mice; *Interferons/metabolism; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Xenograft Model Antitumor Assays; Bhlhe40; Brriar; Breast cancer; Immune response; Interferon signaling; LncRNA; Long noncoding RNA; Rig-i
Research Division(s): Genetics and Gene Regulation
PubMed ID: 41501810
Publisher's Version: https://doi.org/10.1186/s12943-025-02510-8
Open Access at Publisher's Site: https://doi.org/10.1186/s12943-025-02510-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-29 02:00:46

Last Modified: 2026-01-29 02:01:03