Triple-negative breast cancer (TNBC) is particularly sensitive to cyclin-dependent kinase 7 inhibitor, THZ1, compared to hormone receptor (HR)+ breast cancer, but our data found that different TNBC cell lines had a wide range of IC50 values of THZ1, suggesting a possible heterogeneity in sensitivity to THZ1 in TNBC. To seek potential biomarkers of THZ1 sensitivity, we re-analyzed the mRNAs profile in breast cancer cells treated with THZ1 from the previous study and demonstrated that elevated expression of SOX9 was significantly associated with the sensitivity of THZ1 in TNBC. We also verified that SOX9 expression promoted cell proliferation, migration, stemness, and predicted poor prognosis. Moreover, based on the tissue array of 278 patients and over 900 samples from TCGA data, we found that SOX9 expression was significantly higher in TNBC than HR+ breast cancers. Furthermore, ChIP-sequencing indicated that SOX9 binding to enhancer near transcription factor FOXC1, was remarkably inhibited by THZ1. And we also demonstrated that SOX9 and FOXC1 interacted with each other, which might co-operate and co-regulate the MYC signaling pathway in TNBC. Mechanistically, SOX9 may sensitize TNBC cells to THZ1, in a FOXC1-related manner, suggesting that SOX9 could be as a predictive factor of THZ1.

中文翻译：

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SOX9与FOXC1相互作用以激活MYC并调节三阴性乳腺癌中CDK7抑制剂的敏感性。

与激素受体（HR）+乳腺癌相比，三阴性乳腺癌（TNBC）对细胞周期蛋白依赖性激酶7抑制剂THZ1尤其敏感，但我们的数据发现，不同的TNBC细胞系的TH50的IC50值范围很广，表明TNBC对THZ1的敏感性可能存在异质性。为了寻找THZ1敏感性的潜在生物标志物，我们重新分析了先前研究中用THZ1处理的乳腺癌细胞中的mRNA谱，并证明SOX9的表达升高与TNBC中THZ1的敏感性显着相关。我们还证实了SOX9的表达促进细胞增殖，迁移，干性，并预测不良预后。此外，根据278位患者的组织阵列和TCGA数据中的900多个样本，我们发现TNBC中的SOX9表达明显高于HR +乳腺癌。此外，ChIP测序表明THX1显着抑制了SOX9与转录因子FOXC1附近增强子的结合。并且我们还证明了SOX9和FOXC1相互作用，这可能在TNBC中协同作用并共同调节MYC信号通路。从机制上讲，SOX9可能以FOXC1相关的方式使TNBC细胞对THZ1敏感，这表明SOX9可以作为THZ1的预测因子。