Microenvironmental G protein‐coupled estrogen receptor‐mediated glutamine metabolic coupling between cancer‐associated fibroblasts and triple‐negative breast cancer cells governs tumour progression

作者：Chongwu He, Meixi Peng, Xiaoqiang Zeng, Hanzhi Dong, Zhengkui Sun, Jiawei Xu, Manran Liu, Liyan Liu, Yanxiao Huang, Zhiqiang Peng, Yuan Qiu, Chunling Jiang, Bin Xu, Tao Yu · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.70131 · 被引用次数：17 · 研究领域：Estrogen and related hormone effects、Cancer, Hypoxia, and Metabolism、Cancer Cells and Metastasis

BACKGROUND: Triple-negative breast cancer (TNBC) is a particularly aggressive type of breast cancer, known for its lack of effective treatments and unfavorable prognosis. The G protein-coupled estrogen receptor (GPER), a novel estrogen receptor, is linked to increased malignancy in various cancers. However, its involvement in the metabolic regulation of cancer-associated fibroblasts (CAFs), a key component in the tumour microenvironment, remains largely unexplored. This study investigates how GPER influences the metabolic interaction between CAFs and TNBC cells, aiming to identify potential therapeutic targets. METHODS: The co-culture system is performed to examine the interaction between CAFs and TNBC cells, with a focus on GPER-mediated glutamine production and release by CAFs and its subsequent uptake and utilization by TNBC cells. The definite roles of microenvironmental GPER/cAMP/PKA/CREB signalling in regulating the expression of glutamine synthetase (GLUL) and lactate dehydrogenase B (LDHB) are further investigated. RESULTS: Our findings reveal that estrogen-activated GPER in CAFs significantly upregulates the expression of GLUL and LDHB, leading to increased glutamine production. This glutamine is then secreted into the extracellular matrix and absorbed by TNBC cells, enhancing their viability, motility, and chemoresistance both in vitro and in vivo. TNBC cells further metabolize the glutamine through the glutamine transporter (ASCT2) and glutaminase (GLS1) axes, whic...