Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, P. R. China.
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, P. R. China.
Cell Commun Signal. 2020 Aug 17;18(1):128. doi: 10.1186/s12964-020-00613-x.
The activation of the NF-κB pathway plays a crucial role in the progression of breast cancer (BCa) and also involved in endocrine therapy resistance. On the contrary to the canonical NF-κB pathway, the effect of the noncanonical NF-κB pathway in BCa progression remains elusive.
BCa tumor tissues and the corresponding cell lines were examined to determine the correlation between RelB and the aggressiveness of BCa. RelB was manipulated in BCa cells to examine whether RelB promotes cell proliferation and motility by quantitation of apoptosis, cell cycle, migration, and invasion. RNA-Seq was performed to identify the critical RelB-regulated genes involved in BCa metastasis. Particularly, RelB-regulated MMP1 transcription was verified using luciferase reporter and ChIP assay. Subsequently, the effect of RelB on BCa progression was further validated using BCa mice xenograft models.
RelB uniquely expresses at a high level in aggressive BCa tissues, particularly in triple-negative breast cancer (TNBC). RelB promotes BCa cell proliferation through increasing G1/S transition and/or decreasing apoptosis by upregulation of Cyclin D1 and Bcl-2. Additionally, RelB enhances cell mobility by activating EMT. Importantly, RelB upregulates bone metastatic protein MMP1 expression through binding to an NF-κB enhancer element located at the 5'-flanking region. Accordingly, in vivo functional validation confirmed that RelB deficiency impairs tumor growth in nude mice and inhibits lung metastasis in SCID mice. Video abstract.
NF-κB 通路的激活在乳腺癌（BCa）的进展中起着至关重要的作用，并且还涉及内分泌治疗耐药性。与经典的 NF-κB 通路相反，非经典 NF-κB 通路在 BCa 进展中的作用仍不清楚。
检查了 BCa 肿瘤组织和相应的细胞系，以确定 RelB 与 BCa 侵袭性之间的相关性。在 BCa 细胞中操纵 RelB，通过定量检测细胞凋亡、细胞周期、迁移和侵袭来确定 RelB 是否促进细胞增殖和迁移。进行 RNA-Seq 以鉴定涉及 BCa 转移的关键 RelB 调节基因。特别是，使用荧光素酶报告基因和 ChIP 测定验证了 RelB 调节的 MMP1 转录。随后，使用 BCa 小鼠异种移植模型进一步验证了 RelB 对 BCa 进展的影响。
RelB 在侵袭性 BCa 组织中高表达，尤其是在三阴性乳腺癌（TNBC）中。RelB 通过上调 Cyclin D1 和 Bcl-2 增加 G1/S 期转换和/或减少细胞凋亡来促进 BCa 细胞增殖。此外，RelB 通过激活 EMT 增强细胞迁移。重要的是，RelB 通过与位于 5'侧翼区的 NF-κB 增强子元件结合，上调骨转移蛋白 MMP1 的表达。因此，体内功能验证证实，RelB 缺失可损害裸鼠肿瘤生长并抑制 SCID 小鼠肺转移。视频摘要。
