Differential Cytotoxicity of PVP-Copper Nanoparticles in Breast Cancer Cell Lines: Insights from Basal Transcriptomic Profiles

Breast cancer is a heterogeneous disease comprising molecular subtypes with distinct therapeutic vulnerabilities. Among emerging therapeutic strategies, copper-based nanoparticles have shown anticancer activity. However, whether these responses differ across breast cancer subtypes and which molecular programs underlie copper sensitivity remain poorly understood. We investigated subtype-specific responses to Polyvinylpyrrolidone-assisted copper nanoparticles (CuNP-PVP) in breast cancer cell lines and the molecular programs underlying copper adaptation. CuNP-PVP were synthesized and evaluated in luminal (MCF-7), HER2-positive (SKBR3), and triple-negative (MDA-MB-231) breast cancer cell lines, with transcriptomic analyses integrated with CCLE and TCGA-BRCA datasets. UV-Vis spectroscopy revealed a plasmon resonance band at 591 nm, while TEM showed spherical nanoparticles with an average diameter of 76.1 +/- 21.0 nm. DLS indicated a larger hydrodynamic diameter, consistent with PVP coating; {zeta}-potential measurements showed a surface charge of -13 mV, and XPS confirmed mixed reduced and Cu(I)/Cu(II) oxidation states. Exposure to 100 g/mL CuNP-PVP induced subtype-dependent effects on cell viability, with MCF-7 showing greater sensitivity, whereas MDA-MB-231 and SKBR3 were less affected. Baseline transcriptomic analyses revealed enrichment of oxidative stress, metabolic adaptation, and lysosomal programs in less sensitive cells, whereas MCF-7 showed higher expression of lipoylation-related genes. These features supported the development of a Potential Biological Copper-Response Index (PBCRI), which captured subtype-associated transcriptional patterns across independent cell lines and patient tumors, with luminal models showing lower scores and basal/TNBC models showing higher scores. Together, these findings identify candidate transcriptional programs associated with subtype-specific responses to CuNP and provide a framework for investigating potential molecular determinants of copper sensitivity.