目的：谷氨酸草酰乙酸转氨酶2（GPT2）在细胞谷氨酰胺代谢过程中催化丙氨酸和α-酮戊二酸（α-KG）的可逆转氨作用，生成丙酮酸和谷氨酸。谷氨酸可以进一步转化为γ-氨基丁酸（GABA）。然而，GPT2在肿瘤转移中的作用尚不清楚。 方法：使用创面愈合和Transwell实验对乳腺癌细胞迁移和侵袭进行体外分析。RNA测序后进行基因本体论分析，以发现相关的分子功能。随后进行磷酸化蛋白富集的质谱分析，以发现相关的转录因子。最重要的是，使用尾静脉模型和乳腺腺体条件性Gpt2-/-自发性肿瘤小鼠模型评估了GPT2对乳腺癌转移的影响。 结果：GPT2过表达增加了GABA含量，并通过激活GABAA受体促进了乳腺癌的转移。 δ亚单位GABRD对于GPT2 / GABA诱导的乳腺癌转移在异种移植和转基因小鼠模型中是必需的。 Gpt2基因敲除减少了转基因Gpt2-/-小鼠乳腺癌的肺转移，并延长了肿瘤负担小鼠的总生存期。在机制上，GPT2诱导的GABAA受体激活通过打开其相关的钙通道增加了Ca2+内流，而激增的胞内钙离子触发PKC - CREB通路的激活。激活的转录因子CREB通过上调与转移相关的基因表达，如PODXL、MMP3和MMP9，加速了乳腺癌的转移。 结论：总之，本研究表明，GPT2通过上调GABA激活GABAAR-PKC-CREB信号通路促进了乳腺癌的转移，因此成为乳腺癌治疗的潜在靶点。©作者（们）。

Objectives: Glutamic pyruvate transaminase (GPT2) catalyzes the reversible transamination between alanine and α-ketoglutarate (α-KG) to generate pyruvate and glutamate during cellular glutamine catabolism. The glutamate could be further converted to γ-aminobutyric acid (GABA). However, the role of GPT2 in tumor metastasis remains unclear. Methods: The wound healing and transwell assays were carried out to analyze breast cancer cell migration and invasion in vitro. Gene ontology analysis was utilized following RNA-sequencing to discover the associated molecule function. The mass spectrometry analysis following phosphoprotein enrichment was performed to discover the associated transcription factors. Most importantly, both the tail vein model and Mammary gland conditional Gpt2-/- spontaneous tumor mouse models were used to evaluate the effect of GPT2 on breast cancer metastasis in vivo. Results: GPT2 overexpression increases the content of GABA and promotes breast cancer metastasis by activating GABAA receptors. The delta subunit GABRD is necessary for the GPT2/GABA-induced breast cancer metastasis in xenograft and transgenic mouse models. Gpt2 knockout reduces the lung metastasis of the genetic Gpt2-/- breast cancer in mice and prolongs the overall survival of tumor burden mice. Mechanistically, GPT2-induced GABAA receptor activation increases Ca2+ influx by turning on its associated calcium channel, and the surged intracellular calcium triggers the PKC-CREB pathway activation. The activated transcription factor CREB accelerates breast cancer metastasis by upregulating metastasis-related gene expressions, such as PODXL, MMP3, and MMP9. Conclusion: In summary, this study demonstrates that GPT2 promotes breast cancer metastasis through up-regulated GABA activation of GABAAR-PKC-CREB signaling, suggesting it is a potential target for breast cancer therapy.© The author(s).