Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production

• Published in: Scientific reports 2019-08, Vol.9 (1), p.11587-14, Article 11587
• Main Authors: Park, Miso, Kim, Jieun, Phuong, Nguyen T. T., Park, Jung Gyu, Park, Jin-Hee, Kim, Yong-Chul, Baek, Moon Chang, Lim, Sung Chul, Kang, Keon Wook
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/95; 14; 14/19; 59; 631/67/1347; 631/80/84/2336; 64/60; 82; 96; Animals; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; CD63 antigen; Cell Proliferation - drug effects; Estrogens; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; Gelatinase B; Gene expression; Hepatocytes; Humanities and Social Sciences; Humans; Matrix metalloproteinase; MCF-7 Cells; Mesenchyme; Metalloproteinase; Metastases; Metastasis; Mice; multidisciplinary; Neoplasm Metastasis; Proteins; Purinergic P2X Receptor Antagonists - pharmacology; Purinergic P2X Receptor Antagonists - therapeutic use; Receptors, Purinergic P2X7 - drug effects; Receptors, Purinergic P2X7 - metabolism; Science; Science (multidisciplinary); Spleen; Tamoxifen; Tamoxifen - pharmacology; Tamoxifen - therapeutic use
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47734-z

Tamoxifen (TAM) is the standard anti-hormonal therapy for estrogen receptor-positive breast cancer. However, long-term TAM therapy can make acquisition of TAM resistance and there are still no solutions to treat TAM-resistant breast cancer. In this study, we found that protein and mRNA expression of the P2X purinoreceptor 7 (P2X7) was higher in tamoxifen resistant MCF-7 (TAMR-MCF-7) cells than in control MCF-7 cells. P2X7 inhibition potently inhibited the migration of TAMR-MCF-7 cells and the liver metastasis burden of TAMR-MCF-7 cells in the spleen-liver metastasis experiment. However, the P2X7 antagonist did not affect protein expression of matrix metalloproteinase (MMP)-2, MMP-9, and epithelial-mesenchymal transition markers. Here our data indicate a link between small extracellular vesicles (sEV) and P2X7, and suggest a new mechanism of metastasis in TAM-resistant breast cancer cells through P2X7 receptors. The migration of TAMR-MCF-7 cells was increased in a concentration-dependent manner by purified sEV treatment. The number of secreted sEVs and the protein levels of CD63 in TAMR-MCF-7 cells were decreased by the P2X7 antagonist, showing that P2X7 influences the production of sEV. Our results suggest that inhibiting the P2X7 could be considered for metastasis prevention in TAM-resistant cancer patients.