Investigating the mechanism of phthalates in breast cancer using molecular docking and network toxicology

Phthalate esters (PAEs) are ubiquitous environmental contaminants, with certain congeners potentially exhibiting breast cancer-promoting effects. However, their toxicological mechanisms remain poorly characterized. This study systematically investigates PAEs' direct interactions with breast cancer pathways using an integrated computational approach combining molecular docking-based inverse virtual screening with network toxicology. We computational screened 12 representative PAEs against 275 breast cancer-related proteins. Through rigorous network analysis using Cytoscape software with CytoNCA plugin, we identified six pivotal molecular targets: E1A binding protein p300 (EP300), somatic cytochrome c (CYCS), mechanistic target of rapamycin kinase (MTOR), prostaglandin-endoperoxide synthase 2 (PTGS2), peroxisome proliferator-activated receptor gamma (PPARγ), and progesterone receptor (PGR). KEGG pathway enrichment analysis revealed significant associations with two major oncogenic pathways: the cancer pathway and Kaposi's sarcoma-associated herpesvirus (KSHV) infection signaling pathway. Differential gene expression analysis and survival prognosis validation further substantiated these core targets' clinical relevance. Notably, this work identified six pivotal molecular targets (EP300, CYCS, MTOR, PTGS2, PPARγ, and PGR) and for the first time, linked PAEs to the KSHV infection pathway. Our findings establish a novel network toxicology framework for elucidating shared molecular mechanisms underlying PAEs-induced breast carcinogenesis, providing mechanistic insights to support environmental monitoring and preventive strategies against PAEs-associated breast cancer risks.