Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China.
The Second Breast Surgery Department, Jilin Cancer Hospital, Changchun 130012, Jilin, PR China.
Cell Signal. 2024 Dec;124:111383. doi: 10.1016/j.cellsig.2024.111383. Epub 2024 Sep 5.
High expression of low-density lipoprotein receptor related protein 11 (LRP11) has been associated with unfavorable prognosis of breast cancer (BC). This study explores the exact roles of LRP11 in BC progression and investigates the associated mechanism.
LRP11 expression in BC tissues and cells was determined by immunohistochemistry or RT-qPCR. LRP11 upregulation was induced in two human BC cell lines to investigate its impact on cell proliferation, migration, and invasion. Its regulation on immune activity was assessed by detecting PD-L1 protein levels and generating a co-culture system of cancer cells and CD8 T cells. Mouse allograft tumor models were generated to analyze the function of LRP11 in tumorigenesis and immune activity in vivo. Gain-of-function assays of SRY-box transcription factor 13 (SOX13) were performed to investigate its function in development and immunosuppression of BC.
LRP11 was found to be highly expressed in BC tissues and cells, presenting an association with unfavorable prognosis of patients. Artificial upregulation of LRP11 in BC cells triggered malignant properties of cells, enhancing β-catenin-mediated transcriptional activation of PD-L1, thus decreasing immune activity of the co-cultured CD8 T cells. Consistently, LRP11 upregulation in mouse 4 T1 cells and promoted tumorigenesis and immune evasion in mice. SOX13 was found to bind the LRP11 promoter for transcriptional activation. Upregulation of SOX13 similarly promoted growth of BC cells and immunosuppression, with its oncogenic effects blocked by the additional LRP11 knockdown.
This study demonstrates that SOX13 is responsible for LRP11 transcription activation, leading to increased malignant phenotype of BC cells and diminished activity CD8 T cells. This evidence highlights SOX13 and LRP11 as promising novel therapeutic targets to reduce malignant phenotype of BC cells and overcome immunosuppression.
低密度脂蛋白受体相关蛋白 11（LRP11）的高表达与乳腺癌（BC）的不良预后相关。本研究探讨了 LRP11 在 BC 进展中的确切作用，并研究了相关机制。
通过免疫组织化学或 RT-qPCR 检测 BC 组织和细胞中的 LRP11 表达。在两种人 BC 细胞系中诱导 LRP11 上调，以研究其对细胞增殖、迁移和侵袭的影响。通过检测 PD-L1 蛋白水平并生成癌细胞和 CD8 T 细胞的共培养系统来评估其对免疫活性的调节作用。生成小鼠同种异体肿瘤模型以分析 LRP11 在体内肿瘤发生和免疫活性中的功能。进行性盒转录因子 13（SOX13）的功能获得性测定，以研究其在 BC 发生和免疫抑制中的作用。
LRP11 在 BC 组织和细胞中高表达，与患者的不良预后相关。在 BC 细胞中人工上调 LRP11 触发了细胞的恶性特性，增强了 β-连环蛋白介导的 PD-L1 的转录激活，从而降低了共培养的 CD8 T 细胞的免疫活性。一致地，LRP11 在小鼠 4T1 细胞中的上调促进了小鼠的肿瘤发生和免疫逃逸。发现 SOX13 结合 LRP11 启动子进行转录激活。SOX13 的上调同样促进了 BC 细胞的生长和免疫抑制，其致癌作用可被额外的 LRP11 敲低阻断。
本研究表明，SOX13 负责 LRP11 的转录激活，导致 BC 细胞的恶性表型增加和 CD8 T 细胞活性降低。这一证据突出了 SOX13 和 LRP11 作为有前途的新型治疗靶点，可降低 BC 细胞的恶性表型并克服免疫抑制。
