DEHP mediates drug resistance by directly targeting AhR in human breast cancer

Area of Science:

• Oncology
• Environmental Health
• Molecular Biology

Background:

• Chemotherapy and hormonal therapy resistance are significant challenges in breast cancer management, particularly for metastasis and recurrence.
• Di(2-ethylhexyl)phthalate (DEHP) is implicated in drug resistance, but its mechanism remains unclear.

Purpose of the Study:

• To investigate the association between urinary DEHP metabolites and breast cancer recurrence.
• To elucidate the molecular mechanisms by which DEHP contributes to breast cancer drug resistance and progression.

Main Methods:

• Analysis of urinary Σ4MEHP levels in 457 breast cancer patients.
• Correlation analysis of Σ4MEHP levels with clinical parameters and prognostic markers.
• In vitro and in vivo experiments using breast cancer cell lines, zebrafish, and mouse models to assess DEHP's effects on drug response and molecular pathways.

Main Results:

• Significantly higher urinary Σ4MEHP levels in recurrent breast cancer patients compared to non-recurrent cases.
• Positive correlations between Σ4MEHP levels and advanced tumor stage, lymph node involvement, estrogen receptor status, Her2/Neu status, and tumor size.
• DEHP inhibited paclitaxel and doxorubicin efficacy, induced epithelial-mesenchymal transition (EMT) and drug-metabolizing enzymes (CYP2D6, CYP2C8, CYP3A4) via the aryl hydrocarbon receptor (AhR) pathway, and reduced tamoxifen efficacy.

Conclusions:

• Urinary Σ4MEHP is a potential independent prognostic marker for poor survival in breast cancer, especially in Her2/Neu-positive cases.
• DEHP promotes breast cancer recurrence and drug resistance by modulating AhR signaling, leading to EMT and altered drug metabolism.
• Targeting the AhR pathway presents a novel therapeutic strategy for overcoming drug resistance in recurrent breast cancer.