Department of Medicine, McGill University Health Center, Cancer Research Program, 1001 Decarie Blvd, Bloc E, Suite E02.6224, Montreal, QC, H4A 3J1, Canada.
Breast Cancer Res. 2021 Feb 15;23(1):23. doi: 10.1186/s13058-021-01401-2.
Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors.
By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC.
We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo.
Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment.
环氧化酶 2（COX-2）促进三阴性乳腺癌（TNBC）的干性，突出 COX-2 作为这些肿瘤有前途的治疗靶点。然而，迄今为止，在乳腺癌中使用 COX-2 抑制剂的临床试验仅显示出不同的患者反应，没有明显的临床获益，这表明存在导致对 COX-2 抑制剂耐药的潜在分子机制。
通过对人类乳腺癌 RNA-seq 数据进行计算机分析，并对公共患者数据库及其相关转录组、基因组和临床特征进行查询，我们确定了 COX-2 相关基因，其表达与侵袭性 TNBC 特征和对 COX-2 抑制剂的耐药性相关。然后，我们使用 CRISPR 基因敲除方法，在 TNBC 的体外和体内临床前模型中，评估了它们对 TNBC 转移和对 COX-2 抑制剂耐药性的个体贡献。
我们鉴定出多个与 COX-2 相关的基因（TPM4、RGS2、LAMC2、SERPINB5、KLK7、MFGE8、KLK5、ID4、RBP1、SLC2A1），这些基因调节 TNBC 中的肿瘤肺定植。此外，我们发现 TNBC 细胞中 MFGE8 和 KLK5/7 基因表达的沉默显著恢复了对 COX-2 选择性抑制剂的敏感性，无论是在体外还是体内。
总之，我们的研究支持建立和使用新型 COX-2 抑制剂为基础的联合治疗策略，作为 TNBC 治疗的未来策略。
