Chemotherapy-induced uridine diphosphate release promotes breast cancer metastasis through P2Y₆ activation

Although purinergic signaling is important in regulation of immune responses, the therapeutic potential of it in the tumor microenvironment is little defined. In this study, we demonstrate that UDP/P2Y₆ signaling facilitates breast cancer metastasis both in vitro and in vivo. We found that P2Y₆ is not only aberrantly expressed and mutated in most tumor types, but also highly correlated with poor prognosis in breast cancer patients. Furthermore, the migration and invasion of breast cancer cells was obviously increased by UDP and blocked by P2Y₆ specific inhibitor MRS2578 and P2Y₆ shRNA. Similar results was also found in breast cancer cell metastasis mouse model. Interestingly, the endogenous agonist UDP was released significantly by doxorubicin treated cells. In addition, the expression and enzyme activity of MMP-9 were both promoted by UDP and inhibited by MRS2578 or P2Y₆ shRNA. Furthermore, UDP-induced cell invasion was blocked by an MMP-9 inhibitor. Mechanistically, the MAPKs and NF-ΚB signaling pathways, known to be involved in regulation of MMP-9 expression, were both activated by UDP. Taken together, our study reveals a relationship between extracellular danger signals and breast cancer metastasis, which suggests the potential therapeutic significance of UDP/P2Y₆ signaling in cancer therapy.