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Published on: June 9, 2023
SnoRNA U50A mediates everolimus resistance in breast cancer through mTOR downregulation
Jie-Ning Li1, Zhu-Jun Loh2, Hui-Wen Chen3
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Breast Medical Center, National Cheng Kung University Hospital, Tainan, Taiwan; Research Center for Medical Laboratory Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Abstract:
Breast cancer remains the most prevalent cancer in women globally, posing significant challenges in treatment due to the inevitable development of resistance to targeted therapies like everolimus, an mTOR inhibitor. While several mechanisms of resistance have been proposed, the role of snoRNAs in this context remains inadequately explored. Our study unveils a novel connection between snoRNAs and everolimus resistance, focusing on the snoRNA U50A. We discovered that U50A negatively regulates mTOR signaling by transcriptionally downregulating mTOR gene expression, which consequently leads to decreased sensitivity to everolimus treatment. Through RNA sequencing, gene set enrichment analyses, and experimental validations, we established that U50A overexpression in breast cancer cells results in mTOR downregulation and subsequently, everolimus desensitization. Clinical results further supported our findings, showing a higher prevalence of everolimus resistance in tumors with elevated U50A expression. Moreover, our results suggest that U50A's effect on mTOR is mediated through the suppression of the transcription factors c-Myc, with a notable impact on cancer cell viability under everolimus treatment. This study not only highlights the complex role of snoRNAs in cancer drug resistance but also proposes U50A as a potential biomarker for predicting everolimus efficacy in breast cancer treatment.
Insights
Small nucleolar RNA U50A (U50A) promotes everolimus resistance in breast cancer by downregulating mTOR signaling. Elevated U50A levels predict poor response to this targeted therapy, suggesting U50A as a potential resistance biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Breast cancer is the most common cancer in women globally.
- Resistance to targeted therapies like everolimus (an mTOR inhibitor) is a major clinical challenge.
- The role of small nucleolar RNAs (snoRNAs) in cancer drug resistance is not well understood.
Purpose of the Study:
- To investigate the role of snoRNAs in everolimus resistance in breast cancer.
- To identify specific snoRNAs involved in regulating mTOR signaling and treatment response.
- To explore U50A as a potential biomarker for predicting everolimus efficacy.
Main Methods:
- RNA sequencing to identify differentially expressed snoRNAs.
- Gene set enrichment analysis to understand pathway involvement.
- Experimental validation in breast cancer cells (e.g., U50A overexpression).
- Analysis of clinical tumor samples to correlate U50A expression with everolimus resistance.
Main Results:
- U50A was identified as a key regulator of everolimus resistance.
- U50A overexpression leads to downregulation of mTOR gene expression and signaling.
- This downregulation results in decreased sensitivity to everolimus treatment.
- Elevated U50A expression in clinical samples correlated with higher rates of everolimus resistance.
- U50A's mechanism involves suppressing c-Myc transcription factors, impacting cancer cell viability.
Conclusions:
- Small nucleolar RNA U50A plays a significant role in mediating everolimus resistance in breast cancer.
- U50A negatively regulates mTOR signaling, contributing to treatment failure.
- U50A is a potential predictive biomarker for everolimus response in breast cancer patients.
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