Kang Chan Woo, Oh Ju Hun, Wang Eun Kyung, Bao Yaru, Kim Ye Bin, Lee Min-Ho, Lee Yang Jong, Jo Young Seok, Ku Cheol Ryong, Lee Eun Jig
Department of Internal Medicine Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea.
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, College of Medicine, Seoul, South Korea.
iScience. 2024 Jun 9;27(7):110137. doi: 10.1016/j.isci.2024.110137. eCollection 2024 Jul 19.
Pituitary adenoma-induced excess endocrine growth hormone (GH) secretion can lead to breast cancer development and metastasis. Herein, we used an acromegaly mouse model to investigate the role of excess endocrine GH on triple-negative breast cancer (TNBC) growth and metastasis. Additionally, we aimed to elucidate the molecular mechanism of transcription factor 20 (TCF20)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling-mediated aggressiveness and metastasis of TNBC. Excess endocrine GH induced TCF20 activates the transcription of and NRF2-target genes to facilitate TNBC metastasis. Inhibition of GH receptor (GHR) and TCF20 activity using the GHR antagonist or small-interfering RNA-induced gene knockdown resulted in reduced tumor volume and metastasis, suggesting that excess endocrine GH stimulates TCF20/NRF2 pathways in TNBC and promotes metastasis to the lung. GHR inhibitors present an effective therapeutic strategy to prevent TNBC cell growth and metastasis. Our findings revealed functional and mechanistic roles of the GH-TCF20-NRF2 signaling axis in TBNC progression.
垂体腺瘤引起的内分泌生长激素（GH）分泌过多可导致乳腺癌的发生和转移。在此，我们使用肢端肥大症小鼠模型来研究内分泌GH过多对三阴性乳腺癌（TNBC）生长和转移的作用。此外，我们旨在阐明转录因子20（TCF20）/核因子红细胞2相关因子2（NRF2）信号介导的TNBC侵袭性和转移的分子机制。内分泌GH过多诱导TCF20激活NRF2靶基因的转录，以促进TNBC转移。使用GH受体（GHR）拮抗剂或小干扰RNA诱导的基因敲低抑制GHR和TCF20活性，导致肿瘤体积减小和转移减少，表明内分泌GH过多刺激TNBC中的TCF20/NRF2途径并促进肺转移。GHR抑制剂是预防TNBC细胞生长和转移的有效治疗策略。我们的研究结果揭示了GH-TCF20-NRF2信号轴在TBNC进展中的功能和机制作用。
