Background/Objectives: Melatonin is a multifunctional indoleamine with recognized antitumor activity; however, its subtype-specific effects in breast cancer remain incompletely understood. This study aimed to investigate the impact of melatonin on cellular and metabolic processes associated with tumor progression in two human breast cancer cell lines representing distinct molecular subtypes: MCF-7 (luminal A) and MDA-MB-468 (triple-negative). Methods: Breast cancer cells were treated with micromolar concentrations of melatonin, and assays were performed to evaluate cell viability, migration, invasion, mitochondrial status, redox balance, protein expression, and biogenic amine profiles. Results: Melatonin significantly reduced cell viability, migration, and invasion in both cell lines, with more pronounced effects in MCF-7 cells. At the molecular level, melatonin downregulated key metabolic and hypoxia-related proteins, including GAPDH and HIF-1α, while citrate synthase was selectively reduced in MCF-7 cells, indicating suppression of mitochondrial metabolic capacity. This was accompanied by a reduction in mitochondrial status, reflected by decreased MitoGreen staining. Melatonin also induced redox imbalance, as evidenced by increased lipid peroxidation and protein carbonylation, along with subtype-dependent modulation of antioxidant enzymes. In addition, alterations in biogenic amine profiles were observed, suggesting broader metabolic remodeling. Conclusions: Collectively, these findings demonstrate that melatonin exerts subtype-dependent antitumor effects by targeting metabolic, mitochondrial, and redox pathways, supporting further investigation of melatonin as a potential therapeutic adjuvant in breast cancer, while recognizing that the concentrations used in this study exceed physiological circulating levels.
Cesário et al. (Tue,) studied this question.