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3',4'-dimethoxyflavone as an aryl hydrocarbon receptor antagonist in human breast cancer cells
1Department of Veterinary Physiology & Pharmacology, Texas A&M University, 4466 TAMU, College Station, Texas 77843, USA.
Abstract:
Treatment of MCF-7 and T47D human breast cancer cells with 3', 4'-dimethoxyflavone (3',4'-DMF) alone did not induce CYP1A1-dependent ethoxyresorufin O:-deethylase (EROD) activity or reporter gene activity in cells transfected with an aryl hydrocarbon (Ah)-responsive construct (pRNH11c). In contrast, 1 nM 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induced up to a 50- to 80-fold increase in EROD and reporter gene activity in MCF-7 and T47D cells. In cells cotreated with 1 nM TCDD plus 0.1-10 microM 3',4'-DMF, there was a concentration-dependent decrease in the TCDD-induced responses, with 100% inhibition observed at the 10 microM concentration. Gel mobility shift assays using rat liver cytosol and breast cancer cell nuclear extracts showed that 3',4'-DMF alone did not transform the AhR to its nuclear binding form, but inhibited TCDD-induced AhR transformation in rat liver cytosol and blocked TCDD-induced formation of the nuclear AhR complex in MCF-7 and T47D cells. TCDD also inhibited estrogen-induced transactivation in MCF-7 cells, and this response was also blocked by 3',4'-DMF, confirming the AhR antagonist activity of this compound in breast cancer cells.
Insights
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Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- The aryl hydrocarbon receptor (AhR) pathway is implicated in breast cancer.
- Understanding modulators of AhR signaling is crucial for therapeutic development.
Purpose of the Study:
- To investigate the effects of 3',4'-dimethoxyflavone (3',4'-DMF) on AhR activity in human breast cancer cells.
- To determine if 3',4'-DMF acts as an AhR antagonist.
Main Methods:
- Treatment of MCF-7 and T47D cells with 3',4'-DMF and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
- Measurement of CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) and reporter gene activity.
- Gel mobility shift assays to assess AhR transformation and complex formation.
Main Results:
- 3',4'-DMF alone did not activate AhR-mediated gene expression.
- 3',4'-DMF inhibited TCDD-induced EROD and reporter gene activity in a dose-dependent manner.
- 3',4'-DMF blocked TCDD-induced AhR nuclear translocation and also inhibited estrogen-induced transactivation.
Conclusions:
- 3',4'-DMF functions as an AhR antagonist in human breast cancer cells.
- This compound may have potential in modulating pathways relevant to breast cancer progression.