Chronobiological and Metabolic Insights into Triple Negative Breast Cancer (TNBC): A Comparative Analysis

Triple Negative Breast Cancer (TNBC), representing 15-18% of all breast malignancies, is characterized by aggressive behavior, poor prognosis, and limited treatment options due to the absence of estrogen receptor (ER), progesterone receptor (PR), and Her2/neu expression. This study aimed to investigate the chronobiological and metabolic disruptions in TNBC by analyzing circadian secretion patterns of melatonin, cortisol, kynurenic acid, serotonin, and tryptophan in 48 TNBC patients compared to 24 Luminal A breast cancer patients (ER/PR+, Her2/neu-). The results revealed significant differences between the two groups. TNBC patients exhibited markedly reduced melatonin and cortisol levels, reflecting profound circadian dysregulation associated with tumor aggressiveness. Elevated kynurenic acid levels and depleted serotonin highlighted a metabolic shift favoring the kynurenine pathway over serotonin and melatonin synthesis, driven by overexpression of enzymes like indoleamine 2,3-dioxygenase (IDO). Tryptophan levels remained within the normal range, but its metabolic fate was altered, contributing to immune suppression and tumor survival. These findings underscore the critical role of circadian biology and tryptophan metabolism in TNBC progression. The disruption of these pathways not only facilitates tumor growth and immune evasion but also presents opportunities for therapeutic intervention. Potential strategies include melatonin and serotonin supplementation, IDO inhibitors, and approaches aimed at restoring circadian rhythms. This study highlights the potential of these markers as prognostic tools and therapeutic targets, paving the way for improved management of TNBC and advancing our understanding of its systemic effects.