Leptin-Driven Distinct Transcriptional Reprogramming in Triple-Negative Breast Cancer: Implications for Racial Disparities

Obesity is an established risk factor for breast cancer (BC), and leptin, an adipocyte-derived hormone, may link obesity to tumor progression. However, the role of leptin in the molecular heterogeneity of triple-negative breast cancer (TNBC), particularly across racial groups, remains unclear. Here, we examined circulating leptin levels in Black and White women with and without BC and characterized leptin-induced transcriptional changes in TNBC cell lines of White and Black racial backgrounds using RNA sequencing. Functional enrichment analyses were performed using Gene Ontology and KEGG pathway annotations, and clinical relevance was assessed using publicly available datasets. Circulating leptin levels were significantly elevated in women with BC and were relatively higher in Black than White women and associated with increased odds of luminal A and TNBC diagnoses. Leptin induced distinct transcriptional responses in two TNBC cell lines, with differential enrichment of oncogenic, metabolic, and signaling pathways, including spliceosome, steroid biosynthesis, PI3K-AKT, Notch, and extracellular matrix-receptor interaction. Several leptin-responsive genes showed concordant expression in clinical specimens and exhibited race- and subtype- associated differences and prognostic significance. Collectively, these findings identify distinct, context-dependent leptin-responsive transcriptional programs in TNBC and provide insight into their potential contributions to tumor heterogeneity and breast cancer disparities.