Patwardhan Raghavendra S, Rai Archita, Sharma Deepak, Sandur Santosh K, Patwardhan Sejal
Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
Homi Bhabha National Institute, Mumbai, 400094, India.
Heliyon. 2024 Feb 29;10(6):e27011. doi: 10.1016/j.heliyon.2024.e27011. eCollection 2024 Mar 30.
Thioredoxin reductase 1 (Txnrd1) is known to have prognostic significance in a subset of breast cancer patients. Despite the pivotal role of Txnrd1 in regulating several cellular and physiological processes in cancer progression and metastasis, its clinical significance is largely unrecognized. Here, we undertook a retrospective comprehensive meta-analysis of 13,322 breast cancer patients from 43 independent cohorts to assess prognostic and predictive roles of Txnrd1. We observed that Txnrd1 has a positive correlation with tumor grade and size and it is over-expressed in higher-grade and larger tumors. Further, hormone receptor-negative and HER2-positive tumors exhibit elevated Txnrd1 gene expression. Patients with elevated Txnrd1 expression exhibit significant hazards for shorter disease-specific and overall survival. While Txnrd1 has a positive correlation with tumor recurrence and metastasis, it has a negative correlation with time to recurrence and metastasis. Txnrd1 patients exhibit 2.5 years early recurrence and 1.3 years early metastasis as compared to Txnrd1 cohort. Interestingly, patients with high Txnrd1 gene expression exhibit a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they experience early recurrence after radiotherapy. Txnrd1 MDA-MB-231 cells exhibit significant ROS generation and reduced viability after doxorubicin treatment compared to Txnrd1 MCF7 cells. Corroborating with findings from meta-analysis, Txnrd1 depletion leads to decreased survival, enhanced sensitivity to radiation induced killing, poor scratch-wound healing, and reduced invasion potential in MDA-MB-231 cells. Thus, Txnrd1 appears to be a potential predictor of recurrence, metastasis and therapy response in breast cancer patients.
硫氧还蛋白还原酶1（Txnrd1）在一部分乳腺癌患者中具有预后意义。尽管Txnrd1在癌症进展和转移过程中调节多种细胞和生理过程方面发挥着关键作用，但其临床意义在很大程度上尚未得到认识。在此，我们对来自43个独立队列的13322例乳腺癌患者进行了回顾性综合荟萃分析，以评估Txnrd1的预后和预测作用。我们观察到Txnrd1与肿瘤分级和大小呈正相关，并且在高级别和较大肿瘤中过度表达。此外，激素受体阴性和HER2阳性肿瘤表现出Txnrd1基因表达升高。Txnrd1表达升高的患者在疾病特异性生存和总生存方面具有显著的不良预后。虽然Txnrd1与肿瘤复发和转移呈正相关，但它与复发和转移时间呈负相关。与Txnrd1队列相比，Txnrd1患者表现出提前2.5年复发和提前1.3年转移。有趣的是，Txnrd1基因表达高的患者对新辅助化疗表现出病理完全缓解（pCR），但他们在放疗后会出现早期复发。与Txnrd1 MCF7细胞相比，Txnrd1 MDA-MB-231细胞在阿霉素治疗后表现出显著的活性氧生成和活力降低。与荟萃分析的结果一致，Txnrd1缺失导致MDA-MB-231细胞的生存率降低、对辐射诱导杀伤的敏感性增强、划痕伤口愈合不良以及侵袭潜力降低。因此，Txnrd1似乎是乳腺癌患者复发、转移和治疗反应的潜在预测指标。
