Targeting the APOBEC3B-Induced Mutation Showers in Breast Cancer

Abstract : Genomic instability is one of the hallmarks of breast cancer and fuels tumor development as well as metastasis. Recent cancer genomics studies have revealed the cytosine deaminase APOBEC3B is commonly overexpressed in breast cancers, suggesting that it may be an important cause of genomic instability in the context of breast cancer cells. In our studies, we have established cell lines that inducibly express APOBEC3B and the closely related APOBEC3A. Using these cell lines, we found that overexpression of APOBEC3A and APOBEC3B indeed induced genomic instability. Importantly, we found that cells overexpressing APOBEC proteins are highly sensitive to inhibitors of ATR, a master regulator of DNA repair. In contrast, inhibitors of ATM and DNA-PK, two other regulators of DNA repair, did not affect the survival of APOBEC overexpressing cells, suggesting that ATR has a unique role in the repair of APOBEC induced DNA damage. In addition to APOBEC inducible cell lines, we have identified cancer cell lines that express high or low levels of APOBEC. Our preliminary results suggest that high levels of APOBEC in cancer cells render them hypersensitive to ATR inhibitors.