Leptin-driven transcriptional reprogramming in triple-negative breast cancer: Exploring biological drivers of racial disparities

We recently demonstrated that obesity is a significant risk factor for breast cancer (BC) diagnosis with triple-negative and Luminal A subtypes, especially in Black women. Furthermore, obesity was linked to earlier disease onset in Black women, who also demonstrated elevated serum leptin levels, an obesity-associated hormone, that showed a similar epidemiologic association. In this study, we investigated leptin-induced transcriptomic alterations in two triple-negative breast cancer (TNBC) cell lines derived from White (MDA-MB-231) and Black (MDA-MB-468) patients by performing mRNA sequencing, followed by bioinformatic and pathway analyses to identify differentially-expressed genes (DEGs) and their impact on biological pathways. Leptin treatment resulted in widespread gene expression alterations, with 1,857 DEGs identified in MDA-MB-231 and 1,242 DEGs in MDA-MB-468 cells (P < 0.05). Of these DEGs, 1030 and 827 were upregulated, and 617 and 625 were downregulated in MDA-MB-231 and MDA-MB-468, respectively. A comparison of DEGs between MDA-MB-231 and MDA-MB-468 showed only 177 DEGs to be commonly altered, suggesting a diverse and cell line-specific transcriptional impact of leptin signaling. Interestingly, the comparison of sequencing reads from vehicle-treated MDA-MB-231 and MDA-MB-468 cells identified significant transcript-level differences between the two lines. In leptin-treated MDA-MB-231 cells, KEGG pathway analysis revealed enrichment of the spliceosome, steroid biosynthesis, protein export, and basal transcription factor pathways, accompanied by suppression of AMPK signaling, focal adhesion, longevity regulation, and insulin signaling. Conversely, in MDA-MB-468 cells, leptin induced the activation of the ECM-receptor interaction, Notch, PI3K-AKT, and transcriptional misregulation in cancer pathways, while downregulating oxidative phosphorylation, mRNA surveillance, the TCA cycle, and AMPK signaling. Together, these findings suggest that leptin induces distinct, cell line-specific transcriptional reprogramming in TNBC, engaging proliferative signaling pathways, while suppressing energy-sensing and metabolic regulatory networks. Overall, our study highlights that targeting leptin-driven pathways may offer novel therapeutic and preventive opportunities to mitigate the obesity-associated risk of early-onset aggressive breast cancer.