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.

中文翻译：

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RelB 维持内分泌抵抗性恶性肿瘤：深入了解非经典 NF-κB 通路对乳腺癌进展的影响。

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，也与内分泌治疗耐药有关。与经典 NF-κB 通路相反，非经典 NF-κB 通路在 BCa 进展中的作用仍然难以捉摸。检查 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 细胞中操作 RelB，通过定量凋亡、细胞周期、迁移和侵袭来检查 RelB 是否促进细胞增殖和运动。进行 RNA-Seq 来鉴定参与 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 组织中以高水平独特表达，特别是在三阴性乳腺癌 (TNBC) 中。RelB 通过增加 G1/S 转变和/或通过上调 Cyclin D1 和 Bcl-2 减少细胞凋亡来促进 BCa 细胞增殖。此外，RelB 通过激活 EMT 来增强细胞移动性。重要的是，RelB 通过与位于 5' 侧翼区域的 NF-κB 增强子元件结合来上调骨转移蛋白 MMP1 的表达。因此，体内功能验证证实，RelB 缺陷会损害裸鼠的肿瘤生长并抑制 SCID 小鼠的肺转移。