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

TL;DR

The lncRNA BRRIAR influences breast cancer risk by boosting immune responses through interferon signaling, offering a new therapeutic approach for estrogen receptor-positive breast cancer.

Contribution

BRRIAR is identified as a novel lncRNA that modulates interferon signaling both in cis and in trans, linking genetic risk to cancer immunosurveillance.

Findings

BRRIAR is a key target gene at the 3p26 breast cancer risk region and is primarily expressed in ER+ breast tumors.

BRRIAR regulates BHLHE40 in cis and activates RIG-I in trans, triggering interferon signaling and inducing apoptosis in ER+ breast cancer cells.

Overexpression of BRRIAR promotes immune activation in human PBMCs and shows therapeutic potential in ER+ breast cancer xenograft models.

Abstract

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.

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).

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.

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.

The online version contains supplementary material available at 10.1186/s12943-025-02510-8.

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