Oncogenic properties of wild-type DNA repair gene FANCA in breast cancer

FANCA is one of the 23 genes whose deficiencies lead to defective DNA interstrand crosslink repair and cancer-prone Fanconi anemia disease. Beyond its functions in DNA repair and tumor suppression, we report that high FANCA expression is strongly associated with breast cancer development. Overexpression of WT-FANCA significantly promotes breast cancer cell proliferation and tumor growth both in vitro and in vivo, while FANCA deficiency severely compromises the proliferation of breast cancer cells, but not non-tumorigenic breast epithelial cells. Heterozygous knockout of FANCA in breast cancer mouse models is sufficient to cause significant reduction of breast tumor growth in vivo. Furthermore, we have shown that high FANCA expression in breast cancer correlates with promoter hypomethylation in a TET-dependent manner, and TET inhibition recapitulates the proliferation defects caused by FANCA deficiency. Our study identifies the oncogenic properties of WT-FANCA and shows that FANCA is a promising target for breast cancer intervention.