Glucocorticoids (GCs; eg, hydrocortisone [CORT]) are routinely used as chemotherapeutic, anti-emetic, and palliative agents in breast cancer (BCa) therapy. The effects of GC signaling on BCa progression, however, remain a contentious topic as GC treatment seems to be beneficial for receptor-positive subtypes but elicits unfavorable responses in triple-negative BCa (TNBC). The mechanistic basis for these conflicting effects of GC in BCa is poorly understood. In this study, we sought to decipher the molecular mechanisms that govern the GC-dependent induction of the tumor suppressor ERRFI1 gene, an inhibitor of epidermal growth factor receptor (EGFR) signaling, and characterize the role of the GC-ERRFI1 regulatory axis in TNBC. Treatment of TNBC cell lines with a protein synthesis inhibitor or GC receptor (GR) antagonist followed by gene expression analysis suggests that ERRFI1 is a direct GR target. Using in silico analysis coupled with enhancer-reporter assays, we identified a putative ERRFI1 enhancer that supports CORT-dependent transactivation. In orthogonal assays for cell proliferation, survival, migration, and apoptosis, CORT mostly facilitated an oncogenic phenotype regardless of malignancy status. Lentiviral knockdown and overexpression of ERRFI1 showed that the CORT-enhanced oncogenic phenotype is restricted by ERRFI1 in the normal breast epithelial model MCF10A and to a lesser degree in the metastatic TNBC line MDA-MB-468. Conversely, ERRFI1 conferred pro-tumorigenic effects in the highly metastatic TNBC model MDA-MB-231. Taken together, our findings suggest that the progressive loss of the GC-dependent regulation and anti-tumorigenic function of ERRFI1 influences BCa progression and may contribute to the unfavorable effects of GC therapy in TNBC.

中文翻译：

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三阴性乳腺癌中的糖皮质激素依赖性调节和ERRFI1基因功能。

糖皮质激素（GC；例如氢化可的松[CORT]）在乳腺癌（BCa）治疗中常规用作化疗药物，止吐药和姑息药。然而，GC信号传导对BCa进程的影响仍然是一个有争议的话题，因为GC治疗似乎对受体阳性亚型有益，但在三阴性BCa（TNBC）中引起不良反应。尚不清楚GC对BCa产生这些冲突影响的机理基础。在这项研究中，我们试图破译支配肿瘤抑制的GC依赖性诱导的分子机制ERRFI1基因，表皮生长因子受体（EGFR）信号的抑制剂，和表征GC-的作用ERRFI1TNBC中的调节轴。用蛋白质合成抑制剂或GC受体（GR）拮抗剂处理TNBC细胞系，然后进行基因表达分析，表明ERRFI1是直接的GR靶标。使用计算机分析与增强子-报告子分析相结合，我们确定了支持CORT依赖性反式激活的推定ERRFI1增强子。在针对细胞增殖，存活，迁移和凋亡的正交试验中，无论恶性状况如何，CORT大多促进了致癌表型。慢病毒敲低和ERRFI1的过表达结果表明，在正常乳腺上皮模型MCF10A中，CORRT增强的致癌表型受ERRFI1限制，而在转移性TNBC系MDA-MB-468中受较小程度限制。相反，ERRFI1在高度转移性TNBC模型MDA-MB-231中赋予促肿瘤作用。综上所述，我们的发现表明，ERRFI1的GC依赖性调节和抗肿瘤发生功能的逐步丧失会影响BCa的进程，并可能导致TNBC中GC治疗的不利影响。