Integrative Molecular Profiling of miR-548f-3p in Triple-Negative Breast Cancer Highlights ANP32E as a Candidate Downstream Effector

Vollständiger Abstract

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Triple-negative breast cancer (TNBC) remains a major therapeutic challenge due to pronounced molecular heterogeneity, transcriptional plasticity, and frequent treatment resistance. MicroRNA (miRNA)-based strategies have emerged as potential approaches for modulating dysregulated gene expression networks in TNBC; however, the contribution of understudied miRNA families to TNBC-associated regulatory programs remains incompletely understood. This study aimed to investigate the tumor-suppressive role of miR-548f-3p in TNBC and to identify candidate downstream effectors, with particular focus on ANP32E. An integrative analysis combining public transcriptomic datasets, clinical expression profiling, computational target prediction, network-based prioritization, pathway analysis, and single-cell transcriptomic assessment identified miR-548f-3p as consistently downregulated in TNBC. Among candidate downstream targets, ANP32E, a chromatin-associated regulator involved in H2A.Z histone variant dynamics, was identified as a potential effector exhibiting increased expression in TNBC and enrichment within malignant epithelial cell populations. An inverse association between miR-548f-3p and ANP32E expression was observed in patient-derived samples. In breast cancer cell models, miR-548f-3p mimic restoration increased apoptosis, promoted G0/G1 accumulation, and reduced migration- and invasion-associated readouts, although measurable effects were also observed in non-tumorigenic MCF-10A cells. These phenotypic changes were accompanied by reduced ANP32E expression at the protein level, indicating that ANP32E expression is responsive to miR-548f-3p restoration. This study supports miR-548f-3p as a candidate tumor-suppressive miRNA in TNBC. The reduction in ANP32E protein expression following miR-548f-3p restoration, together with computational, single-cell, and clinical expression evidence, supports ANP32E as an expression-responsive candidate downstream effector of miR-548f-3p. Further reporter-based and rescue experiments are required to confirm direct 3′UTR-mediated targeting and to define the mechanistic contribution of ANP32E within the broader miR-548f-3p regulatory network.