WSB-1 regulates DNA repair and the response to DNA damage response inhibitors in breast cancer

Abstract

Tumour hypoxia is a poor prognostic factor and linked with metastatic spread and treatment resistance in most solid tumours, including breast cancer. We previously showed hypoxia-regulated E3 ligase WSB-1s association with poor prognosis in breast cancer. Here, we evaluated the role of WSB-1 in DNA repair regulation in breast cancer, and whether these phenotypes can be exploited therapeutically. WSB-1 knockdown led to transcriptome-wide DNA repair factor upregulation, including homologous recombination (HR) factors BRCA1and RAD51. Reciprocally, WSB-1 overexpression led to downregulation of these repair factors and decreased DNA repair capacity. Patient gene expression datasets analyses also showed an inverse correlation between WSB1 expression vs DNA repair and HR pathways. HR-deficient cancers, including BRCA1/2-deficient breast cancers, are extremely sensitive to PARP inhibitors, a phenotype described as BRCAness. We therefore hypothesised if high WSB-1 expression could be similarly exploited therapeutically. WSB-1 overexpression alone radiosensitised cells and led to increased Olaparib (PARP inhibitor) and Berzosertib (ATR inhibitor) sensitivity in vitro. Our study indicates that WSB-1 expression in breast cancer is associated with modulation of HR factor expression, and we propose that elevated WSB-1 expression could be considered as a potential BRCAness biomarker and promote increased sensitivity to DNA repair targeted therapy in these patients.