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

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.

A matter of delicate balance: Loss and gain of Cockayne syndrome proteins in premature aging and cancer

“…Observations of increased expression of CS proteins in cancer cells and reduction of neoplastic growth by suppression of CS proteins suggest that CS proteins are intimately associated with carcinogenic processes. In corroboration, induction of pro-survival pathways by CS proteins leading to cell robustness and increased proliferation has been recently demonstrated ( Caputo et al, 2013 ; Paccosi et al, 2021 ; Filippi et al, 2022 ). Unlike CS patients, humans afflicted with Werner, Bloom and Rothmund-Thomson syndromes display increased cancer incidence.…”

“…Indeed, upon suppression of CSA or CSB proteins in these cells, several pro-apoptotic factors become dramatically up-regulated leading to a massive induction of apoptosis. Strikingly, ablation of CS proteins specifically affects the tumor cells, without any impact on non-transformed cells, suggesting that the increased expression of CS proteins is crucial for cancer cell survival ( Caputo et al, 2013 ; Paccosi et al, 2021 ; Filippi et al, 2022 ).…”

“…Filippi and collaborators provided the first evidence that Breast Cancer (BC) cells displayed an increased expression of CSA protein, and that its ablation by AntiSense Oligonucleotides (ASOs) drastically impaired the tumorigenicity of BC cells by hampering their survival and proliferative capabilities without affecting normal breast cells. Moreover, CSA ablation also resulted in lowering the IC 50 value of Oxaliplatin and Paclitaxel, two commonly used chemotherapeutic agents in breast cancer treatment ( Filippi et al, 2022 ).…”

“…In addiction to the observation of the dramatic up-regulation of CS proteins in a number of cancer cell lines of different tissue origin ( Caputo et al, 2013 ; Paccosi et al, 2021 ; Filippi et al, 2022 ), it is worth nothing that several groups also provided evidences that many csb single-nucleotide polymorphism (SNPs) are associated with increased cancer susceptibility or affected response to chemotherapy: i) the rs2228526, rs4253160, rs12571445, and rs3793784 SNPs of csb may contribute to the susceptibility of lung cancer ( Lin et al, 2008 ; Ma et al, 2009 ); ii) the SNP rs4253002 has shown a significant association with gastrointestinal toxicity in the patients receiving Platinum-Paclitaxel (TP) regimen, while the SNP rs4253212 has shown to be correlated with neutropenia in the patients receiving Platinum-Gemcitabine (GP) regimen, suggesting that CSB might be involved in regulating clinical outcomes of platinum-based chemotherapy ( Song et al, 2017 ). These data suggest that, almost regarding csb gene, both overexpression and SNPs may contribute to cancer development and progression.…”

“…While mutational loss of functions lead to a different spectrum of abnormalities, mostly correlated with stress-induced cell death and/or cell senescence, increased expression of CS proteins has been reported in cancer cells from different tissues often associated with increased proliferation and cell robustness due to the induction of pro survival pathways ( Spyropoulou et al, 2021 ). In this context, it has been recently demonstrated that inhibition of CS proteins is sufficient to halt neoplastic growth ( Caputo et al, 2013 ; Paccosi et al, 2021 ; Filippi et al, 2022 ). It appears as CS genes act as a double-edged sword whose loss or gain of expression leads to premature aging or cancer respectively.…”