Abstract
Simple SummarySMARCA4 mutations were over-representative in cisplatin resistance and metastatic triple-negative breast cancer (TNBC). Additionally, SMARCA4 inactivation induced the mesenchymal-like subtype TNBC. The epithelial-to-mesenchymal transition and Hippo-YAP/TAZ pathways were activated in SMARCA4 inactivation samples of both SMARCA4 knockout cell lines and TNBC patients. In SMARCA4 knockout cells, the YAP1 inhibitor verteporfin suppressed YAP1 target genes. This study depicts the clinical importance of SMARCA4 depletion in TNBC and suggests YAP/TAZ as a novel target for cisplatin-resistant patients.The role of SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, in genomic organization is well studied in various cancer types. However, its oncogenic role and therapeutic implications are relatively unknown in triple-negative breast cancer (TNBC). We investigated the clinical implication and downstream regulation induced by SMARCA4 inactivation using large-scale genome and transcriptome profiles. Additionally, SMARCA4 was knocked out in MDA-MB-468 and MDA-MB-231 using CRISPR/Cas9 to identify gene regulation and a targetable pathway. First, we observed an increase in SMARCA4 mutations in cisplatin resistance and metastasis in TNBC patients. Its inactivation was associated with the mesenchymal-like (MSL) subtype. Gene expression analysis showed that the epithelial-to-mesenchymal transition (EMT) pathway was activated in SMARCA4-deficient patients. Next, the Hippo pathway was activated in the SMARCA4 inactivation group, as evidenced by the higher CTNNB1, TGF-β, and YAP1 oncogene signature scores. In SMARCA4 knockout cells, EMT was upregulated, and the cell line transcriptome changed from the SL to the MSL subtype. SMARCA4 knockout cells showed cisplatin resistance and Hippo-YAP/TAZ target gene activation. The YAP1 inhibitor verteporfin suppressed the expression of YAP1 target genes, and decreased cell viability and invasiveness on SMARCA4 knockout cells. SMARCA4 inactivation in TNBC endowed the resistance to cisplatin via EMT activation. The YAP1 inhibitor could become a novel strategy for patients with SMARCA4-inactivated TNBC.
Highlights
Triple-negative breast cancer (TNBC) is known to have an aggressive nature with a higher recurrence rate, and more heterogeneous genomic characteristics than other breast cancer subtypes [1,2]
TP53 (76%) and PIK3CA (24%) were the most recurrently mutated genes identified in our TNBC cohort, and ATM, BRCA1 and NF1 mutations were present in more than 10% of the samples (Figure 1A)
The mutations of genes in the PI3K signaling pathway were significantly enriched in the responder group, whereas the mutations in genes related to the SWI/SNF complex (p = 0.056) and protein homeostasis/ubiquitination (p = 0.007) were more frequent among nonresponders (Figure 1A)
Summary
Triple-negative breast cancer (TNBC) is known to have an aggressive nature with a higher recurrence rate, and more heterogeneous genomic characteristics than other breast cancer subtypes [1,2]. Over 30% of TNBC patients present metastases during the disease course or become refractory to treatment [3,4]. There is no effective target therapy for metastatic TNBC [4]. 90% of therapy including cisplatin failed in TNBC metastasis, so chemotherapy resistance is a significant hurdle for metastatic. Novel and combinatorial immunotherapies have been recently proposed, the platinum-based drug cisplatin remains a first-line treatment for TNBC patients [3]. The mutations presented after chemotherapy are not markedly different compared with primary TNBC [6]. These characteristics increase the difficulty of treating cisplatin-relapsed TNBC
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