Ectopic Expression of the Meiotic Protein SYCP2 in Breast Cancer Promotes Homologous Recombination and Endows Broad Resistance to DNA Repair-Targeted Drugs

Drugs targeting the DNA damage response (DDR) pathway are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a component of the meiotic synaptonemal complex, is ectopically expressed in breast cancer and associates with broad resistance to DDR-targeted drugs including Cisplatin, inhibitors for PARP, topoisomerase II and topoisomerase I. SYCP2 overexpression correlates with poor prognosis in breast cancer patients and with decreased survival in a clinical trial of antibody-conjugated topoisomerase I inhibitor. SYCP2 overexpression is sufficient to enhance homologous recombination (HR) and confer DDR-targeted drugresistance. Mechanistically, SYCP2 responds to DNA double strand breaks via its lysine/arginine residues and promotes RAD51 localization to DNA breaks by interacting with RAD51. SYCP2 promotes HR independently of BRCA1, suggesting that SYCP2 is a BRCA-independent determinant of DNA damage sensitivity. Thus, SYCP2, which enhances HR, is potentially a biomarker for breast cancer diagnosis, a predictor of DDR-targeted drug response, a prognostic marker for patient outcome, and a target in breast cancer therapy.