QAP14 suppresses breast cancer stemness and metastasis via activation of dopamine D1 receptor

Ling Yong1, Ye Yao1, Guo-shu Chen2, Xiao-xue Yan2, Yu-chen Guo1, Meng-yi Han1, Jun-sheng Xue1, Wei-zhe Jian1, Tian-yan Zhou1
1 Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
2 Chemical Basic Laboratory, School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou 510006, China
Correspondence to: Tian-yan Zhou:,
DOI: 10.1038/s41401-021-00701-9
Received: 8 January 2021
Accepted: 17 May 2021
Advance online: 28 June 2021


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 D1DR-related mechanisms of QAP14, a new oral compound. 4T1, MDA-MB-231, and D1DR-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 D1DR 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 D1DR 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-κB)/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.
Keywords: metastatic breast cancer; dopamine D1 receptor; cancer stemness; lung metastasis; cell motility; QAP14

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