三阴性乳腺癌 (TNBC) 是乳腺癌的一种侵袭性亚型，缺乏结合雌激素 (ER) 和孕激素 (PR) 的核类固醇受体表达，并且不表现出 HER2（人表皮生长因子 2）受体过度表达。即使面对最初有效的化疗，TNBC 患者也经常会复发。治疗抵抗性肿瘤进展的主要原因之一是细胞应激信号通路的激活。糖皮质激素受体 (GR) 是一种与 PR 最密切相关的皮质类固醇激活转录因子，是内分泌/宿主应激和局部肿瘤微环境 (TME) 衍生的应激反应和细胞应激反应的介质。有趣的是，GR 表达与 ER 乳腺癌的良好预后相关，但预示着 TNBC 的不良预后。传统上，GR 的转录活性受循环糖皮质激素的调节。此外，GR 受配体非依赖性信号传导事件的调节。值得注意的是，应激激活蛋白激酶 p38 MAP 激酶响应 TME 衍生的生长因子和细胞因子（包括 HGF 和 TGFβ1），在丝氨酸 134 (Ser134) 处磷酸化 GR。 Phospho-Ser134-GR (p-Ser134-GR) 与细胞质和核信号分子相关，包括 14-3-3 z、芳烃受体 (AhR) 和缺氧诱导因子 (HIF)。含有 Phospho-GR/HIF 的转录复合物上调基因组，其蛋白质产物包括诱导致癌信号通路 (PTK6) 的成分，进一步促进 TNBC 中癌细胞的存活、化疗耐药性、代谢改变和迁移/侵袭行为。最近的研究表明配体 p-Ser134-GR (p-GR) 参与地塞米松介导的 TNBC 细胞运动和代谢失调相关基因的上调。在此，我们回顾了 GR 的肿瘤促进作用，并讨论了配体依赖性和配体非依赖性/应激信号驱动的 p-GR 输入如何汇聚以协调转移性 TNBC 进展。版权所有 © 2024 Elsevier Ltd。保留所有权利。

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the nuclear steroid receptors that bind estrogens (ER) and progestogens (PRs) and does not exhibit HER2 (Human epidermal growth factor 2) receptor overexpression. Even in the face of initially effective chemotherapies, TNBC patients often relapse. One primary cause for therapy-resistant tumor progression is the activation of cellular stress signaling pathways. The glucocorticoid receptor (GR), a corticosteroid-activated transcription factor most closely related to PR, is a mediator of both endocrine/host stress and local tumor microenvironment (TME)-derived and cellular stress responses. Interestingly, GR expression is associated with a good prognosis in ER+ breast cancer but predicts poor prognosis in TNBC. Classically, GR's transcriptional activity is regulated by circulating glucocorticoids. Additionally, GR is regulated by ligand-independent signaling events. Notably, the stress-activated protein kinase, p38 MAP kinase, phosphorylates GR at serine 134 (Ser134) in response to TME-derived growth factors and cytokines, including HGF and TGFβ1. Phospho-Ser134-GR (p-Ser134-GR) associates with cytoplasmic and nuclear signaling molecules, including 14-3-3ζ, aryl hydrocarbon receptors (AhR), and hypoxia-inducible factors (HIFs). Phospho-GR/HIF-containing transcriptional complexes upregulate gene sets whose protein products include the components of inducible oncogenic signaling pathways (PTK6) that further promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC. Recent studies have implicated liganded p-Ser134-GR (p-GR) in dexamethasone-mediated upregulation of genes related to TNBC cell motility and dysregulated metabolism. Herein, we review the tumor-promoting roles of GR and discuss how both ligand-dependent and ligand-independent/stress signaling-driven inputs to p-GR converge to orchestrate metastatic TNBC progression.Copyright © 2024 Elsevier Ltd. All rights reserved.