Targeting Obesity-Associated Breast Cancer: Curcumin Counteracts Leptin-Induced Tumorigenic and Metastatic Traits in MCF-7 and MDA-MB-231 Breast Cancer Cells

Obesity-driven hyperleptinemia is a key driver of breast cancer (BC) aggressiveness; nevertheless, strategies to counteract leptin-mediated tumor progression remain limited. Curcumin, a natural polyphenol with established anti-obesity, anti-inflammatory, and anticancer properties, has emerged as a promising metabolic and tumor-modulating biomolecule, although its effects on leptin-induced oncogenic signaling remain unclear. This study evaluated Curcumin as an adjuvant nutraceutical against leptin-induced oncogenesis in MCF-7 and MDA-MB-231 cells. Cells were exposed to obesity-mimicking leptin levels alone or with non-toxic Curcumin doses. MTT, clonogenic, wound-healing, and 3D spheroid dissemination assays were used to assess phenotypic changes, while network pharmacology and molecular docking explored underlying mechanisms. Curcumin significantly inhibited leptin-induced proliferation (8–17%), colony formation (60–90%), migration (20–45%), and 3D spheroid dissemination (20%) in both BC cell lines. Network pharmacology identified shared hub proteins, including AKT1, RHOA, MAP2K1, and MAPK14, linking Curcumin targets with leptin-driven BC signatures, and molecular docking supported direct interactions of Curcumin with these proteins. These findings suggest that Curcumin counteracts hyperleptinemia-induced tumor progression by targeting the PI3K/AKT, MAPK/ERK, and RHOA/ROCK pathways. This integrated in vitro and in silico study supports Curcumin as a promising adjuvant nutraceutical for obesity-associated BC, although experimental pathway validation is still required.