Tumor CTR1 Expression and Systemic Copper Dynamics Converge on a Copper Axis in High-Grade Triple-Negative Breast Cancer.

UNLABELLED: Copper (Cu) metabolism represents a unique vulnerability in cancer. CTR1 (SLC31A1) mediates cellular Cu uptake, but its relationship with tumor aggressiveness and neoadjuvant response is unclear. We tested whether tumor SLC31A1 expression and systemic Cu dynamics reflect a coordinated tumor-systemic Cu axis in breast cancer. Baseline tumor SLC31A1 gene expression was analyzed in a retrospective cohort of 1,632 neoadjuvant-treated patients with breast cancer, 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 ΔCu, defined as the posttreatment to pretreatment change in serum Cu, was assessed by subtype, grade, and response, whereas baseline serum Cu was examined by tumor size. Baseline SLC31A1 expression was higher in triple-negative breast cancer (TNBC) nonresponders than in responders (P = 0.0021), particularly in grade 3 tumors (P = 0.0035), with no differences in luminal subtypes. In the prospective cohort, ΔCu changes were most pronounced in TNBC and were strongly grade-dependent: all grade 3 TNBCs showed posttherapy Cu elevation, whereas all grade 2 TNBCs showed decreases (P = 0.034). The relapsed TNBC nonresponder exhibited persistently positive ΔCu, whereas nonresponders from other subtypes showed near-zero or negative changes (P = 0.011). Baseline serum Cu was higher in patients with smaller (T1) versus larger (T2-T3) tumors (P = 0.033). Elevated baseline tumor SLC31A1 expression and posttherapy systemic Cu increases converge in high-grade TNBC, indicating a potential coordinated Cu mobilization program linked to aggressive biology and neoadjuvant resistance.

SIGNIFICANCE: SLC31A1 expression was evaluated in a large retrospective cohort, providing robust evidence that elevated baseline SLC31A1 in high-grade TNBC associates with nonresponse. ΔCu dynamics were assessed in a prospective cohort. Despite the limited size, the consistent ΔCu increase in grade 3 TNBC and a relapsing nonresponder supports a biologically meaningful resistance signal. Together, these datasets define a coordinated Cu axis warranting prospective validation and early Cu-targeted intervention.