Bisphenol A drives nuclear factor-kappa B signaling activation and enhanced motility in non-transformed breast cells

Abstract

Bisphenol A (BPA) is a chemical compound found in a wide range of everyday consumer products, resulting in human exposure. BPA has been described as an endocrine disruptor, affecting different systems of the human body. Notably, nanomolar levels of BPA have been detected in human matrices, including plasma and milk. BPA exposure has been associated with the development of breast cancer, and the increase in breast cancer incidence prompted us to investigate the effects of BPA in MCF10A, a model of non-transformed mammary epithelium. Cells were treated with 10 nM BPA for 24 h to capture early molecular alterations preceding phenotypic transitions. Comprehensive transcriptomic analyses were conducted to identify differentially expressed genes and enriched signaling pathways. Subsequent validations included assessment of cytokine release, protein expression, immunofluorescence for subcellular localization of Nuclear Factor-Kappa B (NF-κB), and evaluation of actin cytoskeletal organization. Transcriptome analysis revealed enrichment in interleukin signaling and activation of the NF-κB pathway following BPA exposure. Functional assays demonstrated that BPA treatment enhanced cell motility, accompanied by increased phosphorylation of NF-κB. Inhibition of NF-κB effectively mitigated BPA-induced effects, including augmented cell motility, nuclear translocation of NF-κB, and cytoskeletal rearrangements. Notably, inhibition of the Mitogen-Activated Protein Kinase (MAPK) pathway, and to a lesser extent of the AKT pathway, counteracted BPA-induced NF-κB activation and the associated increase in cell motility. In conclusion, we show that nanomolar concentration of BPA induces significant changes in the molecular setting and behaviour of non-tranformed breast cells, activating NF-κB signalling that in turn controls inflammation, cell cycle, proliferation and cell motility. Our findings indicate that nanomolar concentrations of BPA can induce significant molecular and behavioral changes in non-transformed breast epithelial cells. These results contribute to a deeper understanding of how environmental pollutants like BPA may perturb breast epithelial cell function and potentially contribute to carcinogenesis.

Keywords: Bisphenol A (BPA); Cell motility; Endocrine-disrupting chemicals; Mammary cells; NF-kB signaling.