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

A Correction to this article was published on 26 January 2022

This article has been updated


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.

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Fig. 1: QAP14 suppressed stemness and tumor growth of metastatic breast cancer.
Fig. 2: QAP14 inhibited the motility of metastatic breast cancer cells.
Fig. 3: The anti-metastasis effect and preliminary safety evaluation of QAP14 in 4T1 allograft model.
Fig. 4: QAP14 activated D1DR in 4T1 cells.
Fig. 5: D1DR antagonist SCH partially antagonized the regulatory effects of QAP14 on metastatic breast cancer.
Fig. 6: D1DR knockout reversed the inhibitory efficacy of QAP14 on metastatic breast cancer.
Fig. 7: QAP14 regulated NF-κB/Akt pathways and EMT process in 4T1 cells.
Fig. 8: The underlying mechanisms involved in the inhibitory effects of QAP14 via D1DR activation on breast cancer metastasis to the lung.

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This project was supported by the Beijing Municipal Natural Science Foundation (Grant No. 7192100) and National Natural Science Foundation of China (Grant No. 82073919).

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Study conception and design: TYZ and LY; data acquisition: LY, GSC, XXY, YCG, and MYH; data analysis and interpretation: LY, YY, and JSX; manuscript drafting: LY, YY, and WZJ; critical revision: TYZ.

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Correspondence to Tian-yan Zhou.

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Yong, L., Yao, Y., Chen, Gs. et al. QAP14 suppresses breast cancer stemness and metastasis via activation of dopamine D1 receptor. Acta Pharmacol Sin 43, 1001–1012 (2022).

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  • metastatic breast cancer
  • dopamine D1 receptor
  • cancer stemness
  • lung metastasis
  • cell motility
  • QAP14

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