Chronic co-exposure to benzo[a]pyrene and BDE-47 induces malignant transformation of human mammary epithelial cells via dysregulation of the miR-491-5p/VPS28 axis.

Benzo[a]pyrene (B[a]P) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) are widespread environmental pollutants associated with breast carcinogenesis, yet their combined effects remain unclear. In this study, a chronic low-dose exposure model was established using human mammary epithelial MCF-10A cells to investigate co-exposure-induced malignant transformation and underlying mechanisms. Both single and combined exposures promoted proliferation, clonogenicity, epithelial-mesenchymal transition, and tumorigenicity. Notably, co-exposure produced weaker proliferative effects than single exposures, suggesting a potential antagonistic interaction. Mechanistically, miR-491-5p was downregulated, whereas VPS28 expression was upregulated during transformation. Functional assays demonstrated that miR-491-5p suppressed, while VPS28 enhanced, proliferation under single-exposure conditions, but not under co-exposure. Molecular docking suggested potential interactions between VPS28 and both compounds. Overall, co-exposure induces malignant transformation accompanied by miR-491-5p/VPS28 dysregulation; the functional contribution of this axis under co-exposure warrants further investigation.