Multiple molecular subtypes and distinct clinical outcomes in breast cancer, necessitate specific therapy. Moreover, despite the improvements in breast cancer therapy, it remains the fifth cause of cancer-related deaths, indicating the involvement of unknown genes. To identify novel contributors and molecular subtype independent therapeutic options, we report reduced expression of FRG1 in breast cancer patients, which regulates GM-CSF expression via direct binding to its promoter. Reduction in FRG1 expression enhanced EMT and increased cell proliferation, migration, and invasion, in breast cancer cell lines. Loss of FRG1 increased GM-CSF levels which activated MEK/ERK axis and prevented apoptosis by inhibiting p53 in an ERK-dependent manner. FRG1 depletion in the mouse model increased tumor volume, phospho-ERK, and EMT marker levels. The therapeutic potential of anti-GM-CSF therapy was evident by reduced tumor size, when tumors with decreased FRG1 were treated with anti-GM-CSF mAb. We found an inverse expression pattern of FRG1 and phospho-ERK levels in breast cancer patient tissues, corroborating the in vitro and mouse model-based findings. Our findings first time elucidate the role of FRG1 as a metastatic suppressor of breast cancer by regulating the GM-CSF/MEK-ERK axis.

乳腺癌的多种分子亚型和不同的临床结果需要特定的治疗。此外，尽管乳腺癌治疗有所改进，但它仍然是癌症相关死亡的第五大原因，表明未知基因的参与。为了确定新的贡献者和独立于分子亚型的治疗选择，我们报告了乳腺癌患者中 FRG1 的表达减少，它通过直接结合其启动子来调节 GM-CSF 的表达。在乳腺癌细胞系中，FRG1 表达的降低增强了 EMT 并增加了细胞增殖、迁移和侵袭。FRG1 的缺失增加了 GM-CSF 水平，从而激活 MEK/ERK 轴并通过以 ERK 依赖性方式抑制 p53 来防止细胞凋亡。小鼠模型中 FRG1 的消耗增加了肿瘤体积、磷酸化 ERK 和 EMT 标志物水平。当 FRG1 减少的肿瘤用抗 GM-CSF mAb 治疗时，抗 GM-CSF 治疗的治疗潜力通过减小肿瘤大小而明显。我们在乳腺癌患者组织中发现了 FRG1 和磷酸化 ERK 水平的反向表达模式，证实了基于体外和小鼠模型的发现。我们的研究结果首次阐明了 FRG1 通过调节 GM-CSF/MEK-ERK 轴作为乳腺癌转移抑制因子的作用。