CSA Antisense Targeting Enhances Anticancer Drug Sensitivity in Breast Cancer Cells, including the Triple-Negative Subtype

SIMPLE SUMMARY: Breast cancer (BC), the most frequent malignancy in woman, shows a high rate of cancer recurrence and resistance to treatment, particularly in Triple-Negative Breast Cancer (TNBC) subtype. Starting from the observation that different subtypes of BC cells, including the TNBC one, display an increased expression of Cockayne Syndrome group A (CSA) protein, which is involved in multiple functions such as DNA repair, transcription and in conferring 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 affecting normal breast cells. Suppression of CSA does result in lowering the IC(50) value of Oxaliplatin and Paclitaxel, two commonly used chemotherapeutic agents in breast cancer treatment, allowing the use of a very low dose of chemotherapeutic that is non-toxic to the normal breast cell line. Finally, CSA ablation restores drug sensitivity in oxaliplatin-resistant cells. Based on these findings, we can conclude that CSA may be a very attractive target for the development of new specific anticancer therapies. ABSTRACT: 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.