Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists,such as trifluoperazine and thioridazine,are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs).In this study,we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL),an atypical antipsychotic,against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms.Oral administration of SUL (25,100 mg.kg-1.d-1) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model,but dose-dependently decreased the proportion of CSCs in vitro and in vivo.In contrast,combination therapy of SUL (50 mg-kg-1.d-1) and DEX (8 mg·kg-1·d-1) markedly suppressed the tumor growth in MCF-7/ Adr xenograft model with littie systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model.Among the metastasis-associated biomarkers analyzed,the combination therapy significantly decreased the levels of MMP-2,but increased E-cadherin levels in 4T1 xenograft tumors.Moreover,the combination therapy significantly inhibited the cell colony formation,migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro.Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues.Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR,which might result from the eradication of CSCs.