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DUOXA1/NIP1, originally identified as a Numb-interacting protein, was recently shown to function as a maturation factor for the dual oxidase 1(DUOX1). In this study, we identified DUOXA1/NIP1 expression in breast cancer cells, observed high expression of DUOXA1 in non-invasive MCF7 cells and low expression in highly metastatic cells with impaired p53 functions linking the expression of DUOXA1 with p53. An inhibition of cell proliferation associated with upregulation of p21Cip1/WAF1 was observed in MDA-MB-231 cells following transfection of DUOXA1. The transient DUOXA1 overexpression also inhibited expression of cell-surface integrin αVβ5 and CD9, which is associated with impaired spreading ability. However, there was no difference in expression of these proteins in DUOX1-depleted cells. The observed effects coincided with an increase in reactive oxygen species (ROS) generation. Our data also demonstrate that DUOXA1 transient overexpression affected the cell–cell adhesion by modulating the actin cytoskeleton, and sensitized cells to doxorubicin. [ABSTRACT FROM AUTHOR]