Filippi Silvia, Paccosi Elena, Balzerano Alessio, Ferretti Margherita, Poli Giulia, Taborri Juri, Brancorsini Stefano, Proietti-De-Santis Luca
Laboratory of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy.
Unit of Molecular Pathology, Department of Experimental Medicine, Section of Terni, University of Perugia, 06100 Perugia, Italy.
Cancers (Basel). 2022 Mar 26;14(7):1687. doi: 10.3390/cancers14071687.
Breast cancer (BC) is the most common cancer with the highest frequency of death among women. BC is highly heterogenic at the genetic, biological, and clinical level. Despite the significant improvements in diagnosis and treatments of BC, the high rate of cancer recurrence and resistance to treatment remains a major challenge in clinical practice. This issue is particularly relevant in Triple-Negative Breast Cancer (TNBC) subtype, for which chemotherapy remains the main standard therapeutic approach. Here, we observed that BC cells, belonging to different subtypes, including the TNBC, display an increased expression of Cockayne Syndrome group A (CSA) protein, which is involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division and that recently was found to confer cell robustness when it is up-regulated. We demonstrated that CSA ablation by AntiSense Oligonucleotides (ASOs) drastically impairs tumorigenicity of BC cells by hampering their survival and proliferative capabilities without damaging normal cells. Moreover, suppression of CSA dramatically sensitizes BC cells to platinum and taxane derivatives, which are commonly used for BC first-line therapy, even at very low doses not harmful to normal cells. Finally, CSA ablation restores drug sensitivity in oxaliplatin-resistant cells. Based on these results, we conclude that CSA might be a very attractive target for the development of more effective anticancer therapies.
乳腺癌（BC）是女性中最常见且致死率最高的癌症。BC在基因、生物学和临床水平上具有高度异质性。尽管BC的诊断和治疗有了显著改善，但癌症的高复发率和治疗耐药性仍是临床实践中的一大挑战。这一问题在三阴性乳腺癌（TNBC）亚型中尤为突出，化疗仍是该亚型主要的标准治疗方法。在此，我们观察到，包括TNBC在内的不同亚型的BC细胞中，科凯恩综合征A组（CSA）蛋白的表达增加，该蛋白参与DNA修复、转录、线粒体稳态和细胞分裂等多种功能，最近发现其上调时可赋予细胞稳健性。我们证明，通过反义寡核苷酸（ASO）去除CSA可通过阻碍BC细胞的存活和增殖能力，而不损害正常细胞，从而显著削弱其致瘤性。此外，抑制CSA可使BC细胞对常用于BC一线治疗的铂类和紫杉烷类衍生物极度敏感，即使在对正常细胞无害的极低剂量下也是如此。最后，去除CSA可恢复奥沙利铂耐药细胞的药物敏感性。基于这些结果，我们得出结论，CSA可能是开发更有效抗癌疗法的一个极具吸引力的靶点。
