Environmental benzophenone exposure promotes breast cancer cell metastasis via the Wnt/β-catenin pathway

Humans, in particular women, are widely exposed to benzophenones, a major supplement in personal care products. However, little is known about the impact of chronic benzophenone exposure on breast cancer progression. In this study, we applied a long-term cell culture model by treating the triple negative breast cancer MDA-MB-231 cells to environmental dosage of 4-hydroxybenzophenone (4HBP), the main metabolite of benzophenones. Interestingly, we found that long-term 4HBP exposure barely altered the growth of MDA-MB-231 cells in vitro, but significantly promoted its migration, invasion, and chemoresistance. Transcriptomic analyses revealed that 4HBP exposure robustly activated the Wnt/β-catenin signaling output in MDA-MB-231 cells. Mechanistically, 4HBP exposure not only upregulated the mRNA and protein expression of β-catenin, but also enhanced its protein stability. Genetic ablation of β-catenin markedly attenuated the 4HBP-induced aggressive phenotype. Lastly, the 4HBP-induced metastatic potential and Wnt/β-catenin pathway activation was validated in a mouse model of lung metastasis. Together, these results suggest that environmental benzophenones exposure may facilitate breast cancer metastasis, and alerts benzophenones exposure to those who already harbor primary breast tumors.