Abstract
BACKGROUND: Copper is an essential nutrient required for energy production, antioxidant defense, and connective tissue maturation, yet has emerged as a metabolic vulnerability in cancer. CTR1 (SLC31A1), the high-affinity copper importer, mediates cellular copper uptake, and its upregulation may signal increased copper demand in tumor cells. The dynamics of copper regulation across tumor growth, aggressiveness, and treatment resistance remain poorly defined in breast cancer. We investigated whether CTR1 expression and systemic copper changes reflect a coordinated tumor-systemic copper axis. METHODS: A retrospective dataset of 1632 breast cancer patients receiving neoadjuvant chemotherapy was analyzed to compare CTR1 gene expression between responders and non-responders across molecular subtypes and tumor grades. Findings were extended to a prospective neoadjuvant cohort in which paired pre- and post-treatment serum copper levels were measured. ΔCopper (post-pre change) was correlated with subtype, grade, response, and tumor size. RESULTS: CTR1 expression was significantly higher in triple-negative breast cancer (TNBC) non-responders than responders (P = 0.0021), particularly in grade 3 tumors (P = 0.0035), with no difference in luminal subtypes. In the prospective cohort, ΔCopper was positive predominantly in TNBC and strongly grade-dependent: all grade 3 TNBCs exhibited copper elevation post-therapy, whereas all grade 2 TNBCs showed negative ΔCopper (P = 0.034). The only relapse in the cohort, a TNBC non-responder, exhibited persistently positive ΔCopper at follow-up and relapse, whereas non-responders from other subtypes showed near-zero or negative ΔCopper (P = 0.011). Baseline serum copper was higher in patients with smaller (clinical T1) versus larger (T2-T3) tumors (P = 0.033). CONCLUSIONS: Parallel CTR1 upregulation in tumors and systemic copper elevation post-therapy suggest a coordinated copper mobilization program in high-grade TNBC. These integrated retrospective and prospective findings link copper transport to therapy response and tumor aggressiveness, highlighting copper biology as a potential therapeutic axis in breast cancer.