Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance.Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl2-treated SK-BR-3 (ER-negative) cells were used to model tumor hypoxia. Protein expression, coimmunoprecipitation, chromatin immunoprecipitation (ChIP), pharmacological inhibition, and siRNA-mediated gene silencing were employed to assess physical and functional interactions. Immunohistochemistry (IHC) on a tissue microarray (TMA) of 168 invasive breast carcinomas was performed to evaluate clinical relevance.Results: ERRα levels remained unchanged under hypoxia, while its coactivator, Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 α (PGC-1α), was upregulated. ERRα physically interacted with HIF-1α and was required for HIF-1 transcriptional activity under hypoxic conditions. ChIP assays showed that ERRα-driven overexpression of Permeability glycoprotein 1 (P-gp) and Vascular Endothelial Growth Factor (VEGF) was mediated by HIF-1α binding to theMDR1andVEGFpromoters. Inhibition or silencing of ERRα reversed P-gp overexpression and restored intracellular doxorubicin. TMA analysis confirmed the clinical correlation between ERRα, HIF-1α, and P-gp expression, highlighting the role of ERRα in hypoxia-induced drug resistance. ERRα expression was independent of ER status, suggesting an estrogen-independent function.Conclusions: This study identifies a novel physical and functional interaction between ERRα and HIF-1α that promotes chemoresistance in hypoxic breast tumors. Targeting ERRα may represent a promising therapeutic strategy to overcome drug resistance in aggressive, ER-independent breast cancer subtypes.
**背景/目的：** HIF-1α与ERRα均参与乳腺癌进展，但二者间的功能相互作用尚不明确。本研究旨在探究其在缺氧诱导的耐药性背景下的分子互作。 **方法：** 使用MCF-7（雌激素受体阳性）细胞球体及CoCl2处理的SK-BR-3（雌激素受体阴性）细胞模拟肿瘤缺氧环境。通过蛋白表达分析、免疫共沉淀、染色质免疫沉淀、药理学抑制及siRNA介导的基因沉默技术，评估其物理与功能相互作用。对包含168例浸润性乳腺癌的组织芯片进行免疫组化分析，以评估临床相关性。 **结果：** 缺氧条件下ERRα水平保持不变，而其共激活因子PGC-1α表达上调。ERRα与HIF-1α发生物理相互作用，且为缺氧条件下HIF-1转录活性所必需。染色质免疫沉淀实验表明，ERRα驱动的P-糖蛋白与血管内皮生长因子过表达，是由HIF-1α结合至MDR1及VEGF启动子所介导。抑制或沉默ERRα可逆转P-糖蛋白过表达并恢复细胞内阿霉素水平。组织芯片分析证实了ERRα、HIF-1α与P-糖蛋白表达之间的临床相关性，凸显了ERRα在缺氧诱导的耐药性中的作用。ERRα的表达与雌激素受体状态无关，提示其具有不依赖于雌激素的功能。 **结论：** 本研究揭示了ERRα与HIF-1α之间存在一种新型的物理与功能相互作用，该作用促进了缺氧性乳腺肿瘤的化疗耐药性。靶向ERRα可能代表一种有前景的治疗策略，用于克服侵袭性、非雌激素受体依赖性乳腺癌亚型的耐药性。
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