Soluble TREM2 drives triple-negative breast cancer progression via activation of the AKT pathway 4650

Description Triggering receptor expressed on myeloid cells 2 (TREM2) plays a key role in immune regulation, particularly within tumor-associated macrophages (TAMs). In triple-negative breast cancer (TNBC), TREM2+ TAMs have been shown to modulate the tumor microenvironment, but the role of its soluble form (sTREM2), produced through proteolytic cleavage, remains unclear. In this study, we investigated the effects of sTREM2 on TNBC progression. In vitro, treatment of TNBC cells with recombinant sTREM2 or sTREM2-containing culture supernatant significantly enhanced cell proliferation, invasion, and migration. These effects were further confirmed by the use of TREM2-neutralizing antibodies, which abrogated sTREM2’s tumor-promoting activities. In vivo, peri-tumoral injections of recombinant sTREM2 led to a notable acceleration of tumor growth in mouse models. Mechanistically, we found that sTREM2 binds to tumor cell transglutaminase 2 (TG2), activating downstream signaling pathways, including the AKT signaling pathway, which mediates its tumor-promoting effects. Furthermore, sTREM2 levels were significantly elevated in the serum of breast cancer patients compared to healthy controls, highlighting its clinical relevance. Collectively, our findings suggest that sTREM2 drives TNBC progression by interacting with TG2 and activating critical tumor cell signaling pathways, positioning it as a potential therapeutic target for TNBC treatment.