Tumor CTR1 expression and systemic copper dynamics converge on a copper axis in high grade triple negative breast cancer

Copper metabolism represents a unique vulnerability in cancer. CTR1 (SLC31A1) mediates cellular copper uptake, but its relationship to tumor aggressiveness and neoadjuvant response is unclear. We tested whether tumor SLC31A1 expression and systemic copper dynamics reflect a coordinated tumor systemic copper axis in breast cancer (BC). Baseline tumor SLC31A1 gene expression was analyzed in a retrospective cohort of 1,632 neoadjuvant-treated breast cancer patients, who were subsequently stratified by pathologic response across molecular subtypes and tumor grades. These findings were extended to an exploratory prospective neoadjuvant cohort, in which △Copper, defined as the post- to pre-treatment change in serum copper, was assessed by subtype, grade, and response, while baseline serum copper was examined by tumor size. Baseline SLC31A1 expression was higher in triple-negative BC (TNBC) non-responders than responders (P = 0.0021), particularly in grade 3 tumors (P = 0.0035), with no differences in luminal subtypes. In the prospective cohort, △copper changes were most pronounced in TNBC and were strongly grade dependent: all grade 3 TNBC showed post-therapy copper elevation, whereas all grade 2 TNBC showed decreases (P = 0.034). The relapsed TNBC non-responder exhibited persistently positive △copper, while non-responders from other subtypes showed near-zero or negative changes (P = 0.011). Baseline serum copper was higher in patients with smaller (T1) versus larger (T2-T3) tumors (P = 0.033). Elevated baseline tumor SLC31A1 expression and post-therapy systemic copper increases converge in high-grade TNBC, indicating a potential coordinated copper mobilization program linked to aggressive biology and neoadjuvant resistance.