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PRMT1 Confers Resistance to Olaparib via Modulating MYC Signaling in Triple-Negative Breast Cancer
Wen-Jing Hsu1,2, Cheng-Hsun Chen1, Yu-Chu Chang1,2
1Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Abstract:
Treatment of triple-negative breast cancer (TNBC) remains an unmet clinical need owing to its lack of an efficient therapeutic target. The targeting of DNA repair by poly(ADP-ribose) polymerase (PARP) inhibitors has shown benefit for patients with the BRCA variation. However, sensitivities to the PARP inhibitors were reported regardless of BRCA status. Thus, exploring the underlying mechanisms is imperative. Herein, we identified that breast cancer cells with an elevated expression of protein arginine methyl transferase 1 (PRMT1) was associated with therapeutic sensitivity to the PARP inhibitor olaparib. The results of cell viability and colony formation assays indicated that the suppression of PRMT1 by small hairpin RNA or by the chemical inhibitor increased sensitivity to olaparib in human TNBC MDA-MB-231 and BT549 cells. Bioinformatic analysis revealed that PRMT1 expression was significantly associated with the MYC signature, and TNBC cells with higher PRMT1 and the MYC signature were associated with therapeutic sensitivity to olaparib. Mechanistic studies further demonstrated that knockdown of PRMT1 reduced the c-Myc protein level and downregulated the expression of MYC downstream targets, whereas overexpression of PRMT1 enhanced c-Myc protein expression. Moreover, the overexpression of PRMT1 promoted c-Myc protein stability, and the inhibition of PRMT1 downregulated c-Myc protein stability. Accordingly, the knockdown of PRMT1 inhibited homologous recombination gene expression. These data indicate that PRMT1 is instrumental in regulating DNA repair, at least in part, by modulating c-Myc signaling. Our data highlighted the PRMT1/c-Myc network as a potential therapeutic target in patients with TNBC.
Insights
Protein arginine methyl transferase 1 (PRMT1) enhances triple-negative breast cancer (TNBC) sensitivity to olaparib by stabilizing c-Myc. Targeting the PRMT1/c-Myc pathway may offer new therapeutic strategies for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, presenting a significant clinical challenge.
- Poly(ADP-ribose) polymerase (PARP) inhibitors show efficacy in BRCA-mutated cancers, but their use extends beyond this, necessitating mechanism exploration.
- Sensitivity to PARP inhibitors varies, indicating underlying regulatory pathways influencing treatment response.
Purpose of the Study:
- To investigate the role of protein arginine methyl transferase 1 (PRMT1) in mediating sensitivity to the PARP inhibitor olaparib in TNBC.
- To elucidate the molecular mechanisms linking PRMT1 expression, c-Myc signaling, and DNA repair in TNBC cells.
- To identify the PRMT1/c-Myc network as a potential therapeutic target for TNBC treatment.
Main Methods:
- Cell viability and colony formation assays were used to assess the impact of PRMT1 suppression on olaparib sensitivity.
- Bioinformatic analysis correlated PRMT1 expression with the MYC signature in TNBC.
- Western blotting and gene expression analysis were employed to study PRMT1's effect on c-Myc protein levels, stability, and downstream targets, as well as homologous recombination gene expression.
Main Results:
- Elevated PRMT1 expression correlated with increased sensitivity to olaparib in TNBC cell lines (MDA-MB-231, BT549).
- Suppression of PRMT1 (via shRNA or chemical inhibitor) enhanced olaparib sensitivity.
- PRMT1 modulated c-Myc protein stability and expression, subsequently affecting MYC downstream targets and homologous recombination gene expression, suggesting PRMT1's role in DNA repair regulation via the c-Myc pathway.
Conclusions:
- PRMT1 plays a crucial role in regulating DNA repair in TNBC, partly through modulating c-Myc signaling.
- The PRMT1/c-Myc axis represents a promising therapeutic target for improving olaparib efficacy in patients with TNBC.
- Targeting PRMT1 could overcome resistance and enhance treatment outcomes for triple-negative breast cancer.
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