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Background <p>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, <i>BRRIAR</i>, which primes the IFN signaling pathway in specific cancer contexts and represents a potential therapeutic strategy for estrogen receptor-positive (ER+) breast cancer.</p> Methods <p><i>BRRIAR</i> expression and subcellular localization were examined using qPCR, in situ hybridization, single-cell RNA sequencing and spatial transcriptomics. <i>BRRIAR</i> 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 <i>BRRIAR</i> was evaluated via intratumoral delivery of lipid nanoparticle-encapsulated <i>BRRIAR</i> in ER + breast cancer xenograft models. Immune activation was assessed using flow cytometry and cytokine profiling of human peripheral blood mononuclear cells (PBMCs).</p> Results <p>We demonstrate that <i>BRRIAR</i> is a key target gene at the 3p26 breast cancer risk region. Primarily expressed in ER + breast tumors, <i>BRRIAR</i> acts both <i>in cis</i> and <i>in trans.</i> Nuclear <i>BRRIAR</i> regulates <i>BHLHE40</i> expression <i>in cis</i> through chromatin interactions, while cytoplasmic <i>BRRIAR</i> binds <i>in trans</i> to the pattern recognition receptor RIG-I, priming IFN signaling. Overexpression of <i>BRRIAR</i> RNA triggers RIG-I signaling, inducing IFN responses, drives rapid, dose-dependent apoptosis of ER + breast cancer cells <i>in vitro</i> and <i>in vivo</i>, and promotes immune activation in human PBMCs.</p> Conclusions <p>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 <i>BRRIAR</i> as a promising lncRNA-based RIG-I activator for ER + breast cancer therapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Haran Sivakumaran,
  • Sneha Nair,
  • Mainá Bitar,
  • Xue Lu,
  • Lu Wang,
  • Ji Liu,
  • Deshapriya S. Karunarathne,
  • P. Prakrithi,
  • Sebastien Jacquelin,
  • Isela Sarahi Rivera,
  • Kristine M. Hillman,
  • Susanne Kaufmann,
  • Rebekah Ziegman,
  • Wei Shi,
  • Sarah Alexandrou,
  • C. Elizabeth Caldon,
  • Rakesh N. Veedu,
  • Quan H. Nguyen,
  • Jonathan Beesley,
  • Michelle N. Wykes,
  • Juliet D. French,
  • Stacey L. Edwards

摘要

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.