PDF(Pubmed)
Abstract：
Triple-negative breast cancer (TNBC) is more aggressive and has a higher metastasis rate compared with other subtypes of breast cancer. Due to the lack of drug-targetable receptors, chemotherapy is now the only available systemic treatment for TNBC. However, some patients might still develop drug resistance and have poor prognosis. Therefore, novel molecular biomarkers and new treatment targets are urgently needed for patients with TNBC. To provide molecular insights into TNBC progression, we investigated the function and the underlying mechanism of Defective in cullin neddylation 1 domain containing 5 (DCUN1D5) in the regulation of TNBC. By TCGA dataset and surgical specimens with immunohistochemical (IHC) staining method, DCUN1D5 was identified to be significantly upregulated in TNBC tumor tissues and negatively associated with prognosis. A series of in vitro and in vivo experiments were performed to confirm the oncogenic role of DCUN1D5 in TNBC. Overexpression of FN1 or PI3K/AKT activator IGF-1 could restore the proliferative and invasive ability induced by DCUN1D5 knockdown and DCUN1D5 could act as a novel transcriptional target of transcription factor Yin Yang 1 (YY1). In conclusion, YY1-enhanced DCUN1D5 expression could promote TNBC progression by FN1/PI3K/AKT pathway and DCUN1D5 might be a potential prognostic biomarker and therapeutic target for TNBC treatment.
摘要：
与其他亚型乳腺癌相比，三阴性乳腺癌（TNBC）更具侵袭性，并且具有更高的转移率。由于缺乏药物靶向受体，化疗是目前TNBC唯一可用的全身治疗方法.然而,部分患者仍可能出现耐药性，预后不良。因此,TNBC患者迫切需要新的分子生物标志物和新的治疗靶点.为了提供对TNBC进展的分子见解，我们研究了含有5个cullinneddylation1结构域（DCUN1D5）在TNBC调控中的功能和潜在机制。通过TCGA数据集和手术标本用免疫组织化学(IHC)染色方法,DCUN1D5在TNBC肿瘤组织中被鉴定为显著上调并且与预后负相关。进行了一系列体外和体内实验以证实DCUN1D5在TNBC中的致癌作用。FN1或PI3K/AKT激活剂IGF-1的过表达可以恢复DCUN1D5敲低诱导的增殖和侵袭能力，DCUN1D5可以作为转录因子阴阳1（YY1）的新转录靶标。总之,YY1增强的DCUN1D5表达可通过FN1/PI3K/AKT途径促进TNBC进展，DCUN1D5可能是TNBC治疗的潜在预后生物标志物和治疗靶点。
