miR-489 induces immunogenic cell death in breast cancer by targeting LAPTM4B

MicroRNA dysregulation plays a critical role in breast cancer progression, yet the functional significance of many microRNAs in tumor biology and antitumor immunity remains incompletely understood. Here, we investigated the expression pattern, clinical relevance, and biological function of miR-489 in breast cancer.

miR-489 expression was analyzed in breast cancer tissues, including basal-like/triple-negative breast cancer (TNBC) cohorts, and correlated with patient survival outcomes. Functional assays were performed in TNBC cell lines following miR-489 restoration to assess effects on cell proliferation, colony formation, and endoplasmic reticulum (ER) stress signaling. Markers of immunogenic cell death, including calreticulin exposure, ATP release, and macrophage-mediated phagocytosis, were evaluated. Mechanistic studies identified and validated target genes using molecular and functional rescue approaches.

miR-489 expression was significantly reduced in breast tumors, particularly in the basal-like/TNBC subtype. Higher miR-489 levels were associated with improved patient survival across independent cohorts. Restoration of miR-489 inhibited proliferation and colony formation in TNBC cells and activated ER stress signaling. miR-489 overexpression also induced features of immunogenic cell death, including increased calreticulin surface exposure, ATP release, and enhanced macrophage phagocytosis. Lysosomal-associated protein transmembrane 4 beta (LAPTM4B) was identified as a direct functional target of miR-489. Suppression of LAPTM4B was required for miR-489-mediated ER stress activation and immunogenic cell death-like responses, while LAPTM4B overexpression partially reversed these effects.

Our findings identify a novel miR-489-LAPTM4B regulatory axis that links tumor suppression with immunogenic cell death in breast cancer. This pathway may represent a potential therapeutic target for improving treatment strategies, particularly in TNBC.