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.

• Authors: Chon-Kit Chou, Hurng-Wern Huang, Chun-Feng Yang, Hans-Uwe Dahms, Shih-Shin Liang, Tsu-Nai Wang, Po-Lin Kuo, Edward Hsi, Eing-Mei Tsai, Chien-Chih Chiu
• Journal: Environmental toxicology (Environ Toxicol) Vol. 34 Issue 4 Pg. 401-414 (Apr 2019) ISSN: 1522-7278 [Electronic] United States
• PMID: 30720231 (Publication Type: Journal Article)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• ESR1 protein, human
• Estrogen Receptor alpha
• Diethylhexyl Phthalate
• Camptothecin

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Breast Neoplasms (genetics, metabolism)
• Camptothecin (pharmacology)
• Cell Proliferation (drug effects, genetics)
• DNA Methylation (drug effects)
• Diethylhexyl Phthalate (toxicity)
• Epigenesis, Genetic (drug effects)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Humans
• MCF-7 Cells