Reduced glutamate decarboxylase 1 underlies morphine-promoted lung metastasis of triple-negative breast cancer in mice

IntroductionMorphine is commonly used for cancer-related pain management. Long-term morphine use is not only addictive but also has been associated with risk factor for cancer. MethodsWe intraperitoneally administered morphine to mice for 14 days and then implanted EO771 cells, triple negative breast cancer cells, into their mammary fat pad. After primary tumors were removed on 38th day, a subset of mice were continuously giving saline or morphine until the 68th day. Tumor size, organ metastasis, and tumor RNA expression were analyzed. ResultsOur results revealed that long-term morphine treatment increased lung metastasis in the triple-negative breast cancer mouse model. To determine cellular pathways responsible for morphine-mediated metastasis, we performed RNA sequencing analysis to compare transcriptional profiles during metastasis. Transcriptional analysis revealed a significant number of genes down-regulated by morphine treatment. Based on pathway analysis, we focused on the novel effect of morphine on down-regulating taurine/hypotaurine biosynthesis. Considering that morphine, droperidol (dopamine receptor antagonist), and naloxone (opioid receptor antagonist) may act through opioid receptor or dopamine receptor, we further demonstrated that taurine reduced EO771 cell invasion caused by morphine, but not by droperidol, or naloxone treatment. In addition, morphine treatment significantly reduced the expression of GAD1, one of the enzymes required for biosynthesis of taurine, whereas droperidol and naloxone did not. ConclusionThese novel findings of morphine reduces GAD1 level and taurine reverses invasion suggest that taurine could potentially be employed as a supplement for triple negative breast cancer patients using morphine as pain management. Key MessagesO_LIMorphine usage has been implicated in modulating immune system and affecting cancer progression. C_LIO_LILong-term usage of morphine promotes metastasis of triple negative breast cancer through reducing taurine biosynthesis. C_LIO_LIThese novel findings of morphine reduces GAD1 level and taurine reverses invasion suggest that taurine could potentially be employed as a supplement for triple negative breast cancer patients using morphine as pain management. C_LI