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.
Highlights
Breast cancer is the most commonly diagnosed heterogeneous malignancy and the leading cause of cancer-related death in women worldwide [1]
To investigate potential genes associated with olaparib resistance, we explored the Genomics of Drug Sensitivity in Cancer (GDSC) database and searched the IC50 value of olaparib and gene expression patterns in various breast cancer cell lines from the Cell Line Encyclopedia (CCLE) datasets
The correlations of olaparib sensitivities with transcriptome-wide mRNA expression in breast cancer cell lines revealed that the protein arginine methyl transferase 1 (PRMT1) gene was within the top ranks (Figure 1A), and breast cancer cells with an elevated expression of PRMT1 were associated with therapeutic resistance to olaparib (Figure 1B)
Summary
Breast cancer is the most commonly diagnosed heterogeneous malignancy and the leading cause of cancer-related death in women worldwide [1]. Breast cancer is stratified into luminal, human epidermal receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC) subtypes, according to the presence of distinct molecular markers, including the estrogen receptor (ER), progesterone receptor (PR), and HER2 [2]. Of all breast cancer cases and is the most malignant subtype of breast cancer because of high heterogeneity, aggressiveness, and lack of treatment options [3,4]. The standard treatment for TNBC is chemotherapy. Patients with TNBC frequently develop resistance [7]. Elucidating the genomic basis and molecular mechanism of chemoresistance in patients with TNBC to explore novel biomarkers is crucial for improving the accuracy of diagnosis and the efficacy of treatments for these patients
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