lncRNA BORG:TRIM28 Complexes Drive Metastatic Progression by Inducing α6 Integrin/CD49f Expression in Breast Cancer Stem Cells.
lncRNA BORG:TRIM28 Complexes Drive Metastatic Progression by Inducing α6 Integrin/CD49f Expression in Breast Cancer Stem Cells.
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DOI：
10.1158/1541-7786.mcr-21-0137
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发表时间：
2021-12
期刊：
影响因子：
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通讯作者：
Schiemann WP
中科院分区：
文献类型：
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作者：
Parker KA;Gooding AJ;Valadkhan S;Schiemann WP
三阴性乳腺癌（TNBC）是乳腺癌中最致命的亚型，其侵袭性表型归因于化疗耐药、转移性播散和快速疾病复发。乳腺癌干细胞（BCSC）是肿瘤发生以及侵袭性致瘤表型获得的重要贡献者，即由于它们具有自我复制和产生异质分化肿瘤细胞的能力。为了阐明 TNBC 中 BCSC 致瘤性的潜在机制，我们确定了长非编码 RNA (lncRNA) BMP/OP 响应基因 (BORG) 作为 BCSC 表型的增强子。事实上，我们发现 BORG 表达：(i) 与干细胞标记 Nanog、Aldh1a3 和 Itga6（α6 整合素/CD49f）相关； (ii) 增强小鼠和人类 TNBC 细胞中的干细胞表型，以及 (iii) 促进小鼠 TNBC 肿瘤的发生。从机制上讲，BORG 通过其与 E3 SUMO 连接酶 TRIM28 物理相互作用的能力促进 BCSC 表型。此外，在 Itga6 的启动子区域观察到 TRIM28 结合，其基因失活可阻止 BORG:TRIM28 复合物：（i）在体外诱导 BCSC 自我更新和扩张，以及（ii）在小鼠肺部引发 BCSC 转移性生长。总的来说，这些发现表明 BORG:TRIM28 复合物是 TNBC 发展和进展中 BCSC 表型的新驱动因素。这项工作确立了 lncRNA BORG 作为 BCSC 表型和 TNBC 攻击行为的驱动因素，这些事件严重依赖于 BORG:TRIM28 复合物的形成和 α6 整合素的表达。
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with its aggressive phenotype being attributed to chemotherapy resistance, metastatic dissemination, and rapid disease recurrence. Breast cancer stem cells (BCSC) are significant contributors to tumor initiation, as well as to the acquisition of aggressive tumorigenic phenotypes, namely due to their ability to self-replicate and to produce heterogeneous differentiated tumor cells. To elucidate the underlying mechanisms that drive BCSC tumorigenicity in TNBC, we identified the long noncoding RNA (lncRNA) BMP/OP-Responsive Gene (BORG) as an enhancer of BCSC phenotypes. Indeed, we found BORG expression to: (i) correlate with stem cell markers Nanog, Aldh1a3, and Itga6 (α6 integrin/CD49f); (ii) enhance stem cell phenotypes in murine and human TNBC cells, and (iii) promote TNBC tumor initiation in mice. Mechanistically, BORG promoted BCSC phenotypes through its ability to interact physically with the E3 SUMO ligase TRIM28. Moreover, TRIM28 binding was observed in the promoter region of Itga6, whose genetic inactivation prevented BORG:TRIM28 complexes from: (i) inducing BCSC self-renewal and expansion in vitro, and (ii) eliciting BCSC metastatic outgrowth in the lungs of mice. Collectively, these findings implicate BORG:TRIM28 complexes as novel drivers of BCSC phenotypes in developing and progressing TNBCs. This work establishes the lncRNA BORG as a driver of BCSC phenotypes and the aggressive behaviors of TNBCs, events critically dependent upon the formation of BORG:TRIM28 complexes and expression of α6 integrin.