Introduction/Rationale: Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options and a poor prognosis. The triggering receptor expressed on myeloid cells 2 (TREM2) is studied in brain immunity but is now emerging as a key player in cancer. It exists in a membrane-bound form and a soluble form (sTREM2), shed from cells. While the role of TREM2 in tumor-associated macrophages is known, the function of sTREM2 in cancer, particularly its direct effect on cancer cells, remains unexplored. This study investigates the hypothesis that sTREM2 directly promotes TNBC progression.
Methods: We measured sTREM2 levels in serum from TNBC patients and healthy controls using ELISA. Human TNBC cell lines were treated with recombinant sTREM2 protein. Cell proliferation, migration, and invasion were assessed using CCK-8, EdU, and Transwell assays. Protein signaling pathways were analyzed by Western blotting. The role of sTREM2 in tumor growth and metastasis was further validated in mouse xenograft models.
Results: sTREM2 levels were significantly higher in TNBC patient serum. Treatment with sTREM2 markedly enhanced the proliferation, migration, and invasion of TNBC cells in vitro. Mechanistically, sTREM2 activated the AKT signaling pathway, as shown by increased phosphorylation of AKT. The oncogenic effects of sTREM2 were blocked by an AKT inhibitor. In mouse models, sTREM2 administration accelerated primary tumor growth and increased the formation of lung metastases.
Conclusion: This study concludes that sTREM2 is a crucial driver of TNBC progression. It acts by directly activating the AKT pathway in cancer cells, promoting aggressive behaviors. These findings identify sTREM2 as a novel prognostic biomarker and a promising therapeutic target for TNBC, potentially leading to new targeted therapies for this challenging disease.
