H2AX mRNA expression reflects DNA repair, cell proliferation, metastasis, and worse survival in breast cancer

The phosphorylated histone variant, gamma-H2AX, is known to play a key role in DNA damage repair. However, the clinical significance of H2AX mRNA expression in breast cancer remains unclear. Utilizing a bioinformatical approach, a total of 3594 breast cancer patients with clinical and transcriptomic data were investigated. Bioinformatical analysis showed that high expression of H2AX is associated with worse disease-free, disease-specific, and overall survival consistently in two independent cohorts. High H2AX expressing tumors were associated with upregulated DNA repair gene sets. Although H2AX was not predictive of chemotherapy response, it was significantly downregulated after effective chemotherapy or radio-chemotherapy. Notably, tumors with high H2AX expression were enriched for DNA replication and MYC targets gene sets, and associated with increased MKI67 expression, suggesting alterations in cell proliferation machinery. H2AX knockdown cells showed decreased cell proliferation as compared to the control cells. Finally, H2AX mRNA expression was higher in the metastatic clones as compared to the parental cells and in the metastatic tumors as compared to the primary tumors in patients, with higher H2AX mRNA expression found in advanced stage cancer patients. In conclusion, high H2AX mRNA expression is associated with increased DNA repair, cell proliferation, metastasis, and worse survival in breast cancer patients.