Mechanism of IL-4 mediated RPL19 promoting malignant progression in HER2 positive breast cancer.

[BACKGROUND] Despite recent improvements in prognosis, breast cancer remains the leading cause of cancer-related mortality in women worldwide. Survival rates vary across breast cancer subtypes. HER2, an oncogene, is amplified in approximately 25% of primary breast cancers and associated with an aggressive clinical course and a poor prognosis. Although HER2-targeted therapies induce significant and durable responses, resistance remains prevalent.RPL19 is coexpressed and positively correlated with HER2.

[METHODS] Analysis of The Cancer Genome Atlas (TCGA) revealed RPL19 upregulation in HER2-amplified breast cancer. Further validation with paired breast cancer and adjacent normal tissues confirmed the differential expression of RPL19 in HER2-amplified breast cancer. In vitro and in vivo functional assays demonstrated that RPL19 promotes the growth and metastasis of HER2-amplified breast cancer cells. Mechanistically, RPL19 upregulates IL-4 via the transcription factor JUN. RPL19 promotes tumor cell proliferation, migration, and invasion, and reduces their sensitivity to trastuzumab through the IL-4/p-STAT6 signaling pathway. In the tumor microenvironment, RPL19 inhibits macrophage-mediated phagocytosis of tumor cells by regulating IL-4 secretion, further promoting tumor progression.

[RESULTS] In summary, RPL19 is overexpressed in HER2-amplified breast cancer and promotes tumor cell growth, metastasis, and reduces their sensitivity to trastuzumab. Through JUN-mediated regulation of IL-4, RPL19 influences the progression and reduces their sensitivity to trastuzumab of HER2-amplified breast cancer via the IL-4/p-STAT6 signaling and IL-4-mediated macrophage phagocytosis pathways.

[CONCLUSIONS] These pathways may represent novel therapeutic targets for HER2-amplified breast cancer.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13058-026-02240-9.