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<p>Breast cancer is a leading cause of cancer mortality in women with triple-negative breast cancer (TNBC) presenting greater treatment challenges due to its aggressive disease progression. Understanding TNBC’s unique cell signaling and gene expression profiles will reveal novel therapeutic strategies.&#xa0;Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as key regulators of gene expression and potential therapeutic targets. This study focuses on a TNBC-enriched lncRNA, non-coding RNA in the aldehyde dehydrogenase 1A pathway (NRAD1, previously LINC00284), which promotes progression in multiple cancers. Our analysis reveals that NRAD1 is central to miRNA–mRNA networks in TNBC cells, mediating cancer-promoting gene expression changes. Fractionation studies showed that NRAD1 is primarily located in the nucleus and mitochondria, with some cytoplasmic presence allowing for transcript-specific competitive endogenous RNA (ceRNA) interactions with miRNAs. However, NRAD1 primarily effects miRNAs independently of ceRNA activity, instead upregulating DICER (a miRNA biogenesis protein), altering sub-cellular distribution, and reducing biogenesis of mitochondria-localized miRNA (i.e., miR-4485-3p). These findings demonstrate novel regulatory interactions between the cancer-promoting lncRNA NRAD1 and miRNAs that alter gene expression in TNBC, expanding our understanding of regulatory lncRNA–miRNA effects, TNBC biology, and highlighting future therapeutic strategies for targeting non-coding RNAs.</p>

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LncRNA NRAD1 regulates the triple-negative breast cancer transcriptome by miRNA biogenesis, localization, and predominately non-ceRNA interactions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月23日

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  • Hannah F. Cahill,
  • Justin M. Brown,
  • Manhattan Leslie-Toogood,
  • Jaganathan Venkatesh,
  • Marie-Claire D. Wasson,
  • Raj Pranap Arun,
  • Meghan E. McLean,
  • Dejan Vidovic,
  • Paola Marcato

摘要

Breast cancer is a leading cause of cancer mortality in women with triple-negative breast cancer (TNBC) presenting greater treatment challenges due to its aggressive disease progression. Understanding TNBC’s unique cell signaling and gene expression profiles will reveal novel therapeutic strategies. Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as key regulators of gene expression and potential therapeutic targets. This study focuses on a TNBC-enriched lncRNA, non-coding RNA in the aldehyde dehydrogenase 1A pathway (NRAD1, previously LINC00284), which promotes progression in multiple cancers. Our analysis reveals that NRAD1 is central to miRNA–mRNA networks in TNBC cells, mediating cancer-promoting gene expression changes. Fractionation studies showed that NRAD1 is primarily located in the nucleus and mitochondria, with some cytoplasmic presence allowing for transcript-specific competitive endogenous RNA (ceRNA) interactions with miRNAs. However, NRAD1 primarily effects miRNAs independently of ceRNA activity, instead upregulating DICER (a miRNA biogenesis protein), altering sub-cellular distribution, and reducing biogenesis of mitochondria-localized miRNA (i.e., miR-4485-3p). These findings demonstrate novel regulatory interactions between the cancer-promoting lncRNA NRAD1 and miRNAs that alter gene expression in TNBC, expanding our understanding of regulatory lncRNA–miRNA effects, TNBC biology, and highlighting future therapeutic strategies for targeting non-coding RNAs.