National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines.
Endocrinology. 2020 Jul 1;161(7). doi: 10.1210/endocr/bqaa082.
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.
糖皮质激素（GC；如，氢化可的松[CORT]）常用于乳腺癌（BCa）治疗的化疗、止吐和姑息治疗药物。然而，GC 信号对 BCa 进展的影响仍然存在争议，因为 GC 治疗似乎对受体阳性亚型有益，但在三阴性乳腺癌（TNBC）中引发不利反应。GC 在 BCa 中产生这些相互矛盾的影响的机制基础理解甚少。在这项研究中，我们试图阐明调控 GC 依赖性诱导肿瘤抑制因子 ERRFI1 基因表达的分子机制，该基因是表皮生长因子受体（EGFR）信号的抑制剂，并研究 GC-ERRFI1 调控轴在 TNBC 中的作用。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，提示 ERRFI1 是直接的 GR 靶基因。通过计算机分析结合增强子报告基因检测，我们鉴定了一个支持 CORT 依赖性转录激活的 ERRFI1 增强子。在细胞增殖、存活、迁移和凋亡的正交测定中，CORT 主要促进致癌表型，而与恶性程度无关。通过慢病毒敲低和 ERRFI1 过表达实验表明，CORT 增强的致癌表型在正常乳腺上皮模型 MCF10A 中受到 ERRFI1 的限制，在转移性 TNBC 细胞系 MDA-MB-468 中限制程度较小。相反，ERRFI1 在高度转移性 TNBC 模型 MDA-MB-231 中赋予促肿瘤发生作用。综上所述，我们的研究结果表明，GC 依赖性调节和 ERRFI1 抑癌功能的逐渐丧失影响 BCa 进展，并可能导致 GC 治疗在 TNBC 中的不利影响。
