Breast cancer is the second leading cause of cancer-related mortality in women,mainly due to metastasis,which is strongly associated with cancer stemness.Our previous studies showed that the eradication of cancer stem-like cells(CSCs)may be related to the activation of dopamine D1 receptor(D1DR).This study aimed to explicitly demonstrate the target-role of D1DR activation in antimetastatic therapy and to investigate the potential efficacy and the underlying D1 DR-related mechanisms of QAP14,a new oral compound.4T1,MDA-MB-231,and D1 DR-knockout 4T1(4T1-D1DR)cells were selected for in vitro study,while 4T1 and 4T1-D1DR cells were further used to establish a mouse allograft model for in vivo study.Our results showed that D1 DR is abundantly expressed in both 4T1 and MDA-MB-231 cells and that knocking out D1DR in 4T1 cells accelerated migration and invasion in vitro as well as lung metastasis in vivo.QAP14 inhibited colony formation,cell motility,mammosphere formation and CSC frequency,induced CSC apoptosis and D1DR expression,and increased cAMP/cGMP levels.Additionally,QAP14 showed inhibitory effects on tumor growth and lung metastasis with acceptable safety in vivo.Knocking out D1 DR almost completely abolished the efficacy,confirming that QAP14 exhibits its anti-CSC and antimetastatic effects through D1DR activation.The underlying mechanisms involved suppression of the nuclear factor κB(NF-KB)/protein kinase B(Akt)pathway and consequent downregulation of both epithelial-to-mesenchymal transition(EMT)process and cancer stemness.In summary,our findings suggest a potential candidate compound,QAP14,as well as a potential target,D1DR,for metastatic breast cancer therapy.

Ling Yong;Ye Yao;Guo-shu Chen;Xiao-xue Yan;Yu-chen Guo;Meng-yi Han;Jun-sheng Xue;Wei-zhe Jian;Tian-yan Zhou

Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System,Department of Pharmaceutics,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China;Chemical BasicLaboratory,School of Chemistry and Chemical Engineering,Guangzhou University,Guangzhou 510006,China

中国药理学报（英文版）

[1]Ling Yong;Ye Yao;Guo-shu Chen;Xiao-xue Yan;Yu-chen Guo;Meng-yi Han;Jun-sheng Xue;Wei-zhe Jian;Tian-yan Zhou-.QAP14 suppresses breast cancer stemness and metastasis via activation of dopamine D1 receptor)[J].中国药理学报（英文版）,2022(04):1001-1012

QAP14,D1DR,antimetastatic,mammosphere

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