Reduced camptothecin sensitivity of estrogen receptor‐positive human breast cancer cells following exposure to di(2‐ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes

Abstract Di(2‐ethylhexyl)phthalate (DEHP) has been considered as an estrogen receptor alpha (ERα) agonist due to its ability to interact with ERα and promote the cell proliferation of ERα‐positive breast cancer cells. The impact of DEHP on the chemical therapy in breast cancer is little known. Two breast cancer cell lines, MCF‐7 (ERα‐dependent) and MDA‐MB‐231 (ERα‐independent) were examined. We found that DEHP impaired the effectiveness of camptothecin (CPT) and alleviated the CPT‐induced formation of reactive oxygen species in ERα‐positive MCF‐7 cells, but not in ERα‐negative MDA‐MB‐231 cells. DEHP also significantly protected MCF‐7 cells against the genotoxicity of CPT. Genome‐wide DNA methylation profiling revealed that after 48 hours of exposure to 100 μM DEHP, MCF‐7 cells exhibited a significant change in their DNA methylation pattern, including hypermethylation of 700 genes and hypomethylation of 221 genes. The impaired therapeutic response to CPT in DEHP‐exposed MCF‐7 cells is probably mediated by epigenetic changes, especially through Wnt/β‐catenin signaling. A zebrafish xenograft model confirmed the disruptive effect of DEHP on CPT‐induced anti‐growth of MCF‐7 cells. In summary, DEHP exposure induces acquired CPT‐resistance in breast cancer cells and epigenetic changes associated with Wnt/β‐catenin signaling activation are probably depending on an ER‐positive status.