ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer. miRNAs play an essential role in TNBC pathogenesis and prognosis. Obesity is linked with an increased risk for several cancers, including breast cancer. Obesity is also related to the dysregulation of miRNA expression in adipose tissues. However, there is limited knowledge about race- and obesity-specific differential miRNA expression in TNBC. We performed miRNA sequencing of 48 samples (24 tumor and 24 adjacent non-tumor tissues) and RNA sequencing of 24 tumors samples from Black (AA) and White (EA) TNBC patients with or without obesity. We identified 55 miRNAs exclusively associated with tumors in obese EA patients and 33 miRNAs in obese AA patients, each capable of distinguishing tumor tissues from obese from lean individuals within their respective racial groups. In EA, we detected 41 significant miRNA–mRNA correlations. Notably, miR-181b-5p and miR-877-5p acted as negative regulators of tumor-suppressor genes (e.g., HEY2, MCL2, HAND2), while miR-204-5p and miR-143-3p appeared to indirectly target oncogenes (e.g., RAB10, DR1, PTBP3, NCBP1). Among AA patients, we found 28 significant miRNA–mRNA interactions. miR-195-5p, miR-130a-3p, miR-130a-5p, miR-424-5p, miR-148a-3p, miR-374-5p, and miR-30a-5p each potentially downregulated two or more genes (e.g., CLCN4, PLCB1, CDC25B, AEBP2, ERBB4). Pathway enrichment analysis highlighted KRAS, ESR1, ESR2, RAB10, TNRC6C, and NCAN as the most commonly differentially expressed in EA, whereas ERBB4, PLCB1, and SERPINE1 were most frequently in AA. These findings highlight the importance of considering race-specific miRNA–mRNA signatures in understanding TNBC in the context of obesity, offering insights into biomarker-driven patient stratification for targeted therapeutic strategies.
