Boettcher Lena, Greimeier Sarah, Borgmann Kerstin, Mughal Shabbir S, Ellinger Bernhard, Bartkowiak Kai, Zobiak Bernd, Failla Antonio V, Steffen Pascal, Claus Ellen, Besler Katharina, Buccitelli Christopher, Schaaf Violetta, Ozga Ann-Kathrin, Parretta Simona, Schneegans Svenja, Mansour Wael Y, Korbel Jan O, Schlueter Hartmut, Brors Benedikt, Pantel Klaus, Wikman Harriet, Werner Stefan
Institute of Tumour Biology, University Medical Centre Hamburg-Eppendorf, 20246, Hamburg, Germany.
Department of Radiotherapy and Radiooncology, University Medical Centre Hamburg-Eppendorf, 20246, Hamburg, Germany.
Breast Cancer Res. 2025 Jul 22;27(1):137. doi: 10.1186/s13058-025-02085-8.
Genome instability is a fundamental feature and hallmark of cancer, associated with aggressiveness, drug resistance and poor prognosis. RAI2 was initially identified as a novel metastasis suppressor protein specifically associated with the presence of disseminated tumour cells in the bone marrow of breast cancer patients, but its molecular function is largely unknown.
We analysed the consequences of RAI2 depletion on gene expression and genomic stability in luminal breast cancer cell lines, performed cytotoxicity profiling using a library of pharmacologically active compounds, and characterized a potential function of the RAI2 protein in the DNA damage response. We performed in silico validation in different breast cancer datasets.
Analysis of clinical samples revealed that in primary breast tumours, low RAI2 gene expression is significantly associated with genomically unstable tumours and poor prognosis. RAI2 depletion in breast cancer cell lines resulted in loss of mitotic fidelity characterized by prolonged mitosis with increased chromosome segregation errors and micronuclei formation. Drug screening revealed increased sensitivity of RAI2-depleted breast cancer cells to topoisomerase I and Aurora A inhibitors. We also found that genotoxic stress induces the RAI2 protein, which has an affinity for and colocalises with poly-(ADP-ribose). We validated the association of RAI2 gene expression with DNA repair capacity in clinical samples.
Our findings support, for the first time, a functional role of RAI2 in the maintenance of genomic stability. Understanding the underlying the molecular mechanism could help to improve patient diagnosis and treatment.
基因组不稳定是癌症的一个基本特征和标志，与侵袭性、耐药性和不良预后相关。RAI2最初被鉴定为一种新型转移抑制蛋白，特别与乳腺癌患者骨髓中播散性肿瘤细胞的存在有关，但其分子功能在很大程度上尚不清楚。
我们分析了RAI2缺失对腔面型乳腺癌细胞系基因表达和基因组稳定性的影响，使用药理活性化合物库进行细胞毒性分析，并表征了RAI2蛋白在DNA损伤反应中的潜在功能。我们在不同的乳腺癌数据集中进行了计算机验证。
对临床样本的分析显示，在原发性乳腺肿瘤中，低RAI2基因表达与基因组不稳定的肿瘤和不良预后显著相关。乳腺癌细胞系中RAI2的缺失导致有丝分裂保真度丧失，其特征是有丝分裂延长，染色体分离错误增加和微核形成。药物筛选显示，RAI2缺失的乳腺癌细胞对拓扑异构酶I和极光激酶A抑制剂的敏感性增加。我们还发现，基因毒性应激可诱导RAI2蛋白，该蛋白与聚（ADP-核糖）具有亲和力并与其共定位。我们在临床样本中验证了RAI2基因表达与DNA修复能力的关联。
我们的研究结果首次支持了RAI2在维持基因组稳定性中的功能作用。了解其潜在的分子机制可能有助于改善患者的诊断和治疗。
