PDF(Pubmed)
Abstract：
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor β (ERβ) in TNBC, but the detailed molecular mechanisms downstream ERβ activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERβ agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERβ were critical for the binding between U2AF1 and ERβ. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERβ-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERβ activation in TNBC, which provides rationale for ERβ activation-based single or combined therapy for patients with TNBC.
摘要：
三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，具有侵袭行为和不良预后。目前可用于TNBC患者的治疗选择主要是化疗。随着我们对这种疾病的理解，新的靶向疗法，包括聚ADP-核糖聚合酶（PARP）抑制剂，抗体-药物缀合物，和免疫检查点抑制剂，已开发用于临床。以前的报道已经证明了雌激素受体β（ERβ）在TNBC中的重要作用，但是TNBC中ERβ激活下游的详细分子机制仍未阐明。在这项研究中,我们证明了一种特定的ERβ激动剂，LY500307在TNBC细胞中有效诱导R环形成和DNA损伤。随后的相互作用组实验表明，U2小核RNA辅助因子1（U2AF1）的残基151至165以及ERβ的Trp439和Lys443对于U2AF1和ERβ之间的结合至关重要。联合RNA测序和核糖体测序分析表明，U2AF1调节的5-氧代脯氨酸酶（OPLAH）的下游RNA剪接可能会影响其酶活性，并且对于ERβ诱导的R环形成和DNA损伤至关重要。在临床样本中，包括来自癌症基因组图谱（TCGA）的115名患者和来自内部队列的32名患者，我们发现ESR2和U2AF1在TNBC患者中的表达密切相关。总的来说，我们的研究揭示了解释ERβ激活在TNBC中的治疗作用的分子机制，这为TNBC患者的基于ERβ激活的单一或联合治疗提供了理论基础。
