Targeting of lactate dehydrogenase C dysregulates the cell cycle and sensitizes breast cancer cells to DNA damage response targeted therapy

The cancer testis antigen (CTA) lactate dehydrogenase C (LDHC) is a promising anticancer target with tumor-specific expression and immunogenicity. Interrogation of breast cancer patient cohorts from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium indicate that upregulation of LDHC expression correlates with unfavorable prognosis. Silencing LDHC in four breast cancer cell lines significantly increased the presence of giant cells, nuclear aberrations, DNA damage, and apoptosis. LDHC-silenced cells demonstrated aberrant cell cycle progression with differential expression of cell cycle checkpoint and DNA damage response regulators. Notably, the clonogenicity of LDHC-silenced cells was further reduced by treatment with the poly polymerase inhibitor olaparib and with the DNA-damaging drug cisplatin...