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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Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.
Gradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18:452–78.
Dittmer J. Breast cancer stem cells: features, key drivers and treatment options. Semin Cancer Biol. 2018;53:59–74.
Antoszczak M. A medicinal chemistry perspective on salinomycin as a potent anticancer and anti-CSCs agent. Eur J Med Chem. 2019;164:366–77.
Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci USA. 2014;111:10574–9.
Shan NL, Wahler J, Lee HJ, Bak MJ, Gupta SD, Maehr H, et al. Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer. J Steroid Biochem Mol Biol. 2017;173:122–9.
Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, et al. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 2010;122:777–85.
Sachlos E, Risueño RM, Laronde S, Shapovalova Z, Lee JH, Russell J, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012;149:1284–97.
Li J, Yao QY, Xue JS, Wang LJ, Yuan Y, Tian XY, et al. Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer. Acta Pharmacol Sin. 2017;38:1282–96.
Yeh CT, Wu AT, Chang PM, Chen KY, Yang CN, Yang SC, et al. Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. Am J Respir Crit Care Med. 2012;186:1180–8.
Wang S, Mou Z, Ma Y, Li J, Li J, Ji X, et al. Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells. Biochem Pharmacol. 2015;95:98–109.
Hao F, Wang S, Zhu X, Xue J, Li J, Wang L, et al. Pharmacokinetic-pharmacodynamic modeling of the anti-tumor effect of sunitinib combined with dopamine in the human non-small cell lung cancer xenograft. Pharmacol Res. 2017;34:408–18.
Yang L, Yao Y, Yong L, Feng Y, Su H, Yao Q, et al. Dopamine D(1) receptor agonists inhibit lung metastasis of breast cancer reducing cancer stemness. Eur J Pharmacol. 2019;859:172499.
Su H, Xue Z, Feng Y, Xie Y, Deng B, Yao Y, et al. N-arylpiperazine-containing compound (C2): An enhancer of sunitinib in the treatment of pancreatic cancer, involving D1DR activation. Toxicol Appl Pharmacol. 2019;384:114789.
Feng Y, Jiao P, Yan X, Xue Z, Yao Y, Yang L, et al. Compound C17 inhibits the lung metastasis of breast cancer. J Chin Pharm Sci. 2019;28:716–27.
Rajendran V, Jain MV. In vitro tumorigenic assay: colony forming assay for cancer stem cells. Methods Mol Biol. 2018;1692:89–95.
Cioce M, Gherardi S, Viglietto G, Strano S, Blandino G, Muti P, et al. Mammosphere-forming cells from breast cancer cell lines as a tool for the identification of CSC-like- and early progenitor-targeting drugs. Cell Cycle. 2010;9:2878–87.
Borcherding DC, Tong W, Hugo ER, Barnard DF, Fox S, LaSance K, et al. Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer. Oncogene. 2016;35:3103–13.
Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. Br J Pharmacol. 2015;172:1–23.
Cherubini E, Di Napoli A, Noto A, Osman GA, Esposito MC, Mariotta S, et al. Genetic and functional analysis of polymorphisms in the human dopamine receptor and transporter genes in small cell lung cancer. J Cell Physiol. 2016;231:345–56.
Yan Y, Pan J, Chen Y, Xing W, Li Q, Wang D, et al. Increased dopamine and its receptor dopamine receptor D1 promote tumor growth in human hepatocellular carcinoma. Cancer Commun (Lond). 2020;40:694–710.
Bourne JA. SCH 23390: the first selective dopamine D1-like receptor antagonist. CNS Drug Rev. 2001;7:399–414.
Jandaghi P, Najafabadi HS, Bauer AS, Papadakis AI, Fassan M, Hall A, et al. Expression of DRD2 is increased in human pancreatic ductal adenocarcinoma and inhibitors slow tumor growth in mice. Gastroenterology. 2016;151:1218–31.
Kline CLB, Ralff MD, Lulla AR, Wagner JM, Abbosh PH, Dicker DT, et al. Role of dopamine receptors in the anticancer activity of ONC201. Neoplasia. 2018;20:80–91.
Sobczuk P, Łomiak M, Cudnoch-Jędrzejewska A. Dopamine D1 receptor in cancer. Cancers. 2020;12:3232.
Jiang K, Yao G, Hu L, Yan Y, Liu J, Shi J, et al. MOB2 suppresses GBM cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling. Cell Death Dis. 2020;11:230.
Kim S, Jee K, Kim D, Koh H, Chung J. Cyclic AMP inhibits Akt activity by blocking the membrane localization of PDK1. J Biol Chem. 2001;276:12864–70.
Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 2010;295:214–28.
Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, et al. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 2010;70:10464–73.
Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114:569–81.
Butti R, Gunasekaran VP, Kumar TVS, Banerjee P, Kundu GC. Breast cancer stem cells: Biology and therapeutic implications. Int J Biochem Cell Biol. 2019;107:38–52.
Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275:36803–10.
Babaei G, Aziz SG, Jaghi NZZ. EMT, cancer stem cells and autophagy; the three main axes of metastasis. Biomed Pharmacother. 2020;133:110909.
Taurin S, Alkhalifa H. Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses. Neoplasia. 2020;22:663–78.
Manuel Iglesias J, Beloqui I, Garcia-Garcia F, Leis O, Vazquez-Martin A, Eguiara A, et al. Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin. PLoS One. 2013;8:e77281.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.
Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA. 2012;109:2784–9.
Guo Y, Yao Q, Kong D, Xue J, Yong L, Li J, et al. Development and validation of a highly sensitive HPLC-MS/MS method for the QAP14, a novel potential anti-cancer agent, in rat plasma and its application to a pharmacokinetic study. J Pharm Biomed Anal. 2020;189:113487.
Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol. 2001; Chapter 20: Unit 20.2.
This project was supported by the Beijing Municipal Natural Science Foundation (Grant No. 7192100) and National Natural Science Foundation of China (Grant No. 82073919).
The authors declare no competing interests.
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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). https://doi.org/10.1038/s41401-021-00701-9
- metastatic breast cancer
- dopamine D1 receptor
- cancer stemness
- lung metastasis
- cell motility
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