Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

中文翻译：

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Matrin 3在基底样乳腺癌中的抑癌作用

基底样乳腺癌（BLBC）或三阴性乳腺癌（TNBC）是人类乳腺癌的一种侵袭性和高度转移性亚型。本研究旨在阐明 MATR3（一种丰富的核蛋白）在 BLBC/TNBC 中的潜在肿瘤抑制功能，其癌症相关性尚未得到表征。我们通过细胞增殖和软琼脂集落形成测定分析体外致瘤性，通过流式细胞术和聚（ADP-核糖）聚合酶（PARP）裂解分析细胞凋亡，通过实时检查特定 EMT 标记来分析上皮间质转化（EMT）定量 PCR 以及通过 Boyden Chamber 测定进行的体外迁移和侵袭。为了阐明 MATR3 作为肿瘤抑制因子发挥作用的潜在机制，我们进行了串联亲和纯化，然后进行质谱 (TAP-MS) 和通路分析。我们还通过对公开的转录组数据集进行生物信息分析，仔细检查了人类乳腺癌不同亚型中的 MATR3 表达水平以及 MATR3 表达与患者生存之间的相关性。MATR3 抑制 BLBC/TNBC 细胞的体外致瘤性，促进细胞凋亡并抑制 EMT、迁移和侵袭。多种调节细胞凋亡的蛋白被鉴定为 MATR3 结合蛋白，并且 YAP/TAZ 通路被 MATR3 抑制。MATR3 表达与乳腺癌的侵袭性和转移性呈负相关。此外，MATR3的高表达水平与乳腺癌患者的良好预后相关。我们的数据表明 MATR3 在 BLBC/TNBC 细胞中充当假定的肿瘤抑制因子。此外，MATR3 还可以作为生物标志物来预测乳腺癌患者的化疗敏感性和患者生存期。