Zhang Y, Song Y, Ren S, Zhang M, Zhang Z, Fan S, Liu X, Peng X, Qi Q, Shen X, Chen Y

Tamoxifen is a first-line therapeutic drug for oestrogen-receptor positive breast cancer; however, like other therapeutics, its clinical use is limited by acquired resistance. Tamoxifen-resistant cells have demonstrated enhanced aerobic glycolysis; however, the mechanisms underlying this upregulation remain unclear. Here, we demonstrated that G-protein coupled oestrogen receptor (GPER) was involved in ...

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the upregulation of aerobic glycolysis via induction of hypoxia-inducible factor-1? (HIF-1?) expression and transcriptional activity in tamoxifen-resistant cells. Additionally, GPER stabilized HIF-1? through inhibiting its hydroxylation and ubiquitin-mediated degradation, which were associated with upregulation of C-terminal hydrolase-L1 (UCH-L1), downregulation of prolyl hydroxylase 2 (PHD2) and von Hippel-Lindau tumour suppressor protein (pVHL), induction of HIF-1?/UCH-L1 interaction, and suppression of HIF-1?/PHD2-pVHL association. The GPER/HIF-1? axis was functionally responsible for regulating tamoxifen sensitivity both in vitro and in vivo. Moreover, there was a positive correlation between GPER and HIF-1? expression in clinical breast cancer tissues, and high levels of GPER combined with nuclear HIF-1? indicated poor overall survival. High levels of the GPER/HIF-1? axis were also correlated with shorter relapse-free survival in patients receiving tamoxifen. Hence, our findings support a critical role of GPER/HIF-1? axis in the regulation of aerobic glycolysis in tamoxifen-resistant cells, offering a potential therapeutic target for tamoxifen-resistant breast cancer.

Date: Jan. 01, 2023

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