Introduction

Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer characterized by rapid metastasis and tumor embolization within lymphatic vessels [1]. Unlike many cancers, IBC cells retain strong epithelial cadherin (E-cadherin) expression, promoting stable cell–cell adhesion and multicellular cluster formation that enhances metastatic dissemination [2]. Disrupting E-cadherin-mediated adhesion may represent a strategy to destabilize tumor emboli and reduce metastatic potential. Cold atmospheric plasma (CAP) generates reactive oxygen and nitrogen species (RONS), including atomic oxygen (O), hydroxyl radicals (OH), hydrogen peroxide (H₂O₂), and singlet oxygen (¹O₂), which can induce oxidative modifications in biomolecules and alter protein–protein interactions in cancer cell adhesion [3].

Methods

All-atom molecular dynamics simulations were performed on the extracellular EC1–EC2 domains of the E-cadherin homodimer, forming the primary adhesive interface between neighboring cells. Oxidative modifications associated with CAP-generated RONS were introduced at oxidation-susceptible residues, including methionine at the adhesive interface. Thermodynamic integration (TI) was employed to compute the change in binding free energy (ΔBFE) upon oxidation. Alchemical transformations were performed for multiple configurations, including native and oxidized states of chain A and combined oxidation scenarios of both chains, enabling systematic evaluation of adhesion energetics.

Results

Preliminary simulations indicate that oxidation of interfacial residues disrupts key stabilizing interactions within the E-cadherin homodimer, including inter-chain hydrophobic contacts and hydrogen bonding networks. In particular, oxidation reduces the number and persistence of inter-chain contacts at the adhesive interface, suggesting decreased binding stability. Ongoing TI calculations will quantify ΔBFE across oxidation states and identify residues that contribute most to adhesion loss.

Conclusions

CAP-induced oxidative stress may weaken E-cadherin–mediated adhesion in IBC by reducing the binding free energy of the E-cadherin interface. This effect could compromise tumor embolus integrity and increase susceptibility to detachment-induced cell death, supporting plasma-based modulation of cell adhesion as a potential adjuvant therapeutic strategy in IBC.