The present study revealed that: (1) NPL4 is up-regulated in BC tissue and is correlated with poor prognosis, (2) overexpression of NPL4 promotes BC cell proliferation, while depletion of NPL4 reduces BC cell proliferation, (3) upregulation of NPL4 leads to elevation of cyclin D1 by enhancing its mRNA stability, (4) NPL4 binds directly to DXO and induces its degradation, and (5) the NPL4/DXO/cyclin D1 axis exerts an critical role in BC cell proliferation and associated with prognosis. This evidence concerns the gene DXO and breast cancer.