Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Breast Cancer Res. 2024 Nov 6;26(1):155. doi: 10.1186/s13058-024-01910-w.
Cancer metastasis remains a major challenge in the clinical management of triple-negative breast cancer (TNBC). The NF-κB signaling pathway has been implicated as a crucial factor in the development of metastases, but the underlying molecular mechanisms remain largely unclear.
PTPN20 expression was evaluated using data from the Sweden Cancerome Analysis Network-Breast and The Cancer Genome Atlas database, as well as by western blotting and immunohistochemistry in 88 TNBC patients. The ability of PTPN20 to activate NF-κB was assessed by luciferase reporter assays. The effects of PTPN20 overexpression and knockdown via short hairpin RNA were examined in TNBC cell lines by wound healing and transwell matrix penetration assays. Additionally, we analyzed the growth and metastasis abilitiy of 4T1 xenograft tumors in nude mice.
PTPN20 levels were elevated in TNBC cell lines and patient samples compared to controls, and higher protein levels correlated with metastasis-free survival. Overexpression of PTPN20 enhanced migration and invasion in vitro, and promoted lung metastasis in vivo. Our finding revealed that PTPN20 activates NF-κB signaling by dephosphorylating p65 at Ser468, preventing its binding to COMMD1, thereby protecting p65 from degradation. Downregulation of PTPN20 effectively inhibit, while p65 S468A mutant restored the migratory and invasive abilities of TNBC cells.
Collectively, our results demonstrate that PTPN20 plays a critical role in TNBC metastasis through the activation of NF-κB signaling. We propose that PTPN20 may serve as a novel prognostic marker and potential therapeutic target for the treatment of TNBC.
癌症转移仍然是三阴性乳腺癌（TNBC）临床治疗的主要挑战。NF-κB 信号通路已被认为是转移发展的关键因素，但潜在的分子机制在很大程度上仍不清楚。
使用瑞典癌症分析网络-乳房和癌症基因组图谱数据库的数据以及对 88 名 TNBC 患者的 Western 印迹和免疫组织化学评估 PTPN20 的表达。通过荧光素酶报告基因检测评估 PTPN20 激活 NF-κB 的能力。通过划痕愈合和 Transwell 基质渗透试验在 TNBC 细胞系中检查 PTPN20 过表达和短发夹 RNA 敲低的影响。此外，我们分析了裸鼠 4T1 异种移植瘤的生长和转移能力。
与对照相比，PTPN20 在 TNBC 细胞系和患者样本中的水平升高，并且较高的蛋白水平与无复发生存相关。PTPN20 的过表达增强了体外迁移和侵袭，并且促进了体内肺转移。我们的研究结果表明，PTPN20 通过去磷酸化 p65 的 Ser468 来激活 NF-κB 信号，从而阻止其与 COMMD1 结合，从而防止 p65 降解。下调 PTPN20 可有效抑制，而 p65 S468A 突变体则恢复了 TNBC 细胞的迁移和侵袭能力。
总的来说，我们的研究结果表明 PTPN20 通过激活 NF-κB 信号在 TNBC 转移中起关键作用。我们提出 PTPN20 可能是 TNBC 治疗的新型预后标志物和潜在治疗靶点。
