Subtype-specific melatonin receptor expression on circulating tumor cells and associated inflammatory/metabolic biomarkers in breast cancer: A 3-year cohort analysis (n=171).

Abstract

e13016 Background: Melatonin signaling modulates inflammation, extracellular matrix remodeling, and tumor metabolism. We investigated whether melatonin receptor expression on circulating tumor cells (CTCs) differs by breast cancer subtype and whether it aligns with systemic biomarkers reflecting inflammation and metabolic reprogramming. Methods: Over three years, 171 breast cancer patients were grouped as triple-negative breast cancer (TNBC), HER2/neu-positive and ER/PR-negative, Luminal A, or Luminal B. Blood and urine were collected for plasma melatonin, urinary melatonin sulfate, matrix metalloproteinases (MMPs), IL-6, TNF-α, and LDH isoenzymes (LDH-1, LDH-5). CTCs were isolated using density gradient centrifugation and immunomagnetic separation; melatonin receptor expression on CTCs was evaluated by flow cytometry and immunocytochemistry. Melatonin was quantified by HPLC; MMPs/cytokines by ELISA; LDH isoenzymes by electrophoretic methods; urinary melatonin sulfate by RIA. Between-group comparisons used one-way ANOVA; correlations used Pearson testing (p < 0.05). Results: Melatonin receptor expression on CTCs was lowest in TNBC, higher in HER2/neu-positive ER/PR-negative, and highest in Luminal subtypes (maximal in Luminal A). TNBC demonstrated an aggressive systemic profile: LDH-1 elevation in 75% (LDH-5 not elevated), IL-6 elevation in 90%, TNF-α in 98%, and significantly decreased melatonin. HER2/neu-positive ER/PR-negative disease showed LDH-5 elevation in 59% with moderate melatonin decrease (IL-6 81%, TNF-α 93%). Luminal B showed LDH-5 elevation in 47% with moderate melatonin decrease (IL-6 72%, TNF-α 95%). Luminal A showed LDH-5 elevation in 35.5% with mild melatonin decrease (IL-6 51%, TNF-α 98.3%). Across subtypes, lower CTC melatonin receptor expression tracked with higher inflammatory cytokines and subtype-specific LDH patterns. Conclusions: Reduced melatonin signaling (lower CTC melatonin receptor expression and lower melatonin) is associated with more aggressive breast cancer biology, particularly TNBC, and aligns with inflammatory activation and distinct metabolic isoenzyme shifts. A combined panel integrating CTC melatonin receptor expression with melatonin/MMPs/cytokines/LDH isoenzymes may support biologic stratification and inform melatonin-based interventional trial hypotheses.