Niazi Farshad, Parker Kimberly A, Mason Sara J, Singh Salendra, Schiemann William P, Valadkhan Saba
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Cancers (Basel). 2024 Sep 23;16(18):3241. doi: 10.3390/cancers16183241.
BACKGROUND/OBJECTIVES: Long noncoding RNAs (lncRNAs) are known to play key roles in breast cancers; however, detailed mechanistic studies of lncRNA function have not been conducted in large cohorts of breast cancer tumors, nor has inter-donor and inter-subtype variability been taken into consideration for these analyses. Here we provide the first identification and annotation of the human BORG lncRNA gene.
METHODS/RESULTS: Using multiple tumor cohorts of human breast cancers, we show that while BORG expression is strongly induced in breast tumors as compared to normal breast tissues, the extent of BORG induction varies widely between breast cancer subtypes and even between different tumors within the same subtype. Elevated levels of BORG in breast tumors are associated with the acquisition of core cancer aggression pathways, including those associated with basal tumor and pluripotency phenotypes and with epithelial-mesenchymal transition (EMT) programs. While a subset of BORG-associated pathways was present in high BORG-expressing tumors across all breast cancer subtypes, many were specific to tumors categorized as triple-negative breast cancers. Finally, we show that genes induced by heterologous expression of BORG in murine models of TNBC both in vitro and in vivo strongly overlap with those associated with high BORG expression levels in human TNBC tumors.
Our findings implicate human BORG as a novel driver of the highly aggressive basal TNBC tumor phenotype.
背景/目的：已知长链非编码RNA（lncRNA）在乳腺癌中发挥关键作用；然而，尚未在大量乳腺癌肿瘤队列中对lncRNA功能进行详细的机制研究，并且在这些分析中也未考虑供体间和亚型间的变异性。在此，我们首次对人类BORG lncRNA基因进行了鉴定和注释。
方法/结果：使用多个人类乳腺癌肿瘤队列，我们发现与正常乳腺组织相比，BORG在乳腺肿瘤中强烈诱导表达，但BORG诱导程度在乳腺癌亚型之间甚至同一亚型内的不同肿瘤之间差异很大。乳腺肿瘤中BORG水平升高与核心癌症侵袭途径的获得有关，包括那些与基底肿瘤和多能性表型以及上皮-间质转化（EMT）程序相关的途径。虽然在所有乳腺癌亚型中高表达BORG的肿瘤中存在一部分与BORG相关的途径，但许多途径是三阴性乳腺癌特有的。最后，我们表明在体外和体内TNBC小鼠模型中，BORG异源表达诱导的基因与人类TNBC肿瘤中与高BORG表达水平相关的基因强烈重叠。
我们的研究结果表明人类BORG是高度侵袭性基底TNBC肿瘤表型的新型驱动因素。
