Abstract
Purpose
Aryl hydrocarbon receptor (AhR) inhibits estrogen receptor (ER) pathway, which may suppress estrogen-dependent cell proliferation. However, the correlation between AhR stimulation and intratumoral estrogen synthesis, especially through aromatase, has not been reported to date. In the present study, we examined this correlation in breast cancer cells.
Methods
We examined AhR and aromatase immunoreactivity in 29 patients with invasive ductal carcinoma. We performed in vitro studies using three breast carcinoma cell lines, MCF-7, T47D, and MDA-MB-231.
Results
AhR stimulation induced the mRNA expression of the aromatase gene in vitro in three breast carcinoma cell lines, and increased estrogen synthesis in MCF-7 cell line. Results of microarray analysis showed that AhR-induced aromatase expression was associated with BRCA1 induction. Analysis of patients with breast cancer showed a significant positive correlation between intratumoral AhR and aromatase status. We also compared the effects of AhR stimulation on the induction of intratumoral estrogen synthesis and inhibition of the ER signaling pathway, because AhR exerts contradictory effects on estrogen action in breast carcinoma cells. AhR-induced aromatase expression persisted for a significantly longer duration than AhR-induced ER pathway inhibition. Moreover, breast carcinoma cells treated with an AhR agonist tended to show earlier cell proliferation after removing the agonist than cells not treated with the AhR agonist.
Conclusion
The results of the present study suggest that AhR stimulates estrogen-dependent progression of breast carcinoma by inducing aromatase expression under some conditions. These results provide new insights on the possible roles of environmental toxins in breast cancer development.
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Abbreviations
- AhR:
-
Aryl hydrocarbon receptor
- Beta-NF:
-
Beta-naphthoflavone
- BRCA1:
-
Breast cancer susceptibility gene 1
- CYP:
-
Cytochrome P450
- DAB:
-
3,3′-Diaminobenzidine
- DMSO:
-
Dimethyl sulfoxide
- E1:
-
Estrone
- E2:
-
Estradiol
- ER:
-
Estrogen receptor
- FBS:
-
Fetal bovine serum
- IDC:
-
Invasive ductal carcinoma
- IL-6:
-
Interleukin-6
- OD:
-
Optical density
- pS2:
-
Estrogen-inducible protein pS2
- RPL13A:
-
Ribosomal protein L13a
- TCDD:
-
2,3,7,8-Tetrachlorodibenzo-p-dioxin
- TNF:
-
Tumor necrosis factor
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Acknowledgements
We gratefully acknowledge Mr. Katsuhiko Ono and Erina Iwabuchi (Tohoku University School of Medicine) for providing excellent technical support.
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Saito, R., Miki, Y., Hata, S. et al. Aryl hydrocarbon receptor induced intratumoral aromatase in breast cancer. Breast Cancer Res Treat 161, 399–407 (2017). https://doi.org/10.1007/s10549-016-4063-x
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DOI: https://doi.org/10.1007/s10549-016-4063-x