• Estrogen could enhance the cytotoxicity of PARP inhibitors on ER-positive breast cancer cells by affecting the expression of BRCA1 and DNA repair. • The impact of estrogen on PARP inhibition is due to the induction of nitric oxide that can be resembled by exogenous nitric oxide donors. • Stimulation of NO suppressed BRCA1 and led to accumulation of DNA damages, which is underlying the impact of estrogen on PARP inhibitors. • This study revealed a novel link between hormone level and the efficacy of PARP inhibitors, which should be considered during therapy. Inhibition of Poly(ADP-ribose) polymerase (PARP) is effective for breast cancer susceptibility genes 1 (BRCA1)-deficient breast cancers. Although hormones play critical roles on the occurrence as well as being used in conventional therapies of breast cancer, their impacts on PARP-targeted therapy have been poorly addressed. Here, we showed that addition of estrogen could enhance the cytotoxicity of PARP inhibitors on estrogen receptor (ER)-positive breast cancer cells, causing significant suppression of cell growth. Further analysis revealed that the impact was due to estrogen's stimulating the production of nitric oxide (NO), which could be abrogated when blocking NO formation. Moreover, the effect of estrogen can be resembled by two exogenous nitric oxide donors (SNAP and GSNO). Using ER-negative cell line MDA-MB231, estrogen could not enhance the cell killing of PARP inhibitors any more, but addition of NO donors re-established the enhancing effects. The increased NO level led to accumulation of DNA double strand breaks (DSBs) based on the formation of H2AX foci. Consistent with earlier studies, we demonstrated that NO suppressed the expression of BRCA1, a key player involved in DSB recombination repair. Taken together, these data reveal an important role of estrogen on the treatment of PARP inhibitors, which may affect its clinical treatment and should be considered in precision therapies for ER-positive and negative cancers. [ABSTRACT FROM AUTHOR]