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Aryl hydrocarbon receptor induced intratumoral aromatase in breast cancer

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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

References

  1. Klinge CM, Bowers JL, Kulakosky PC, Kamboj KK, Swanson HI (1999) The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements. Mol Cell Endocrinol 157(1–2):105–119

    Article  CAS  PubMed  Google Scholar 

  2. Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y, Kato S (2003) Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423(6939):545–550. doi:10.1038/nature01606

    Article  CAS  PubMed  Google Scholar 

  3. Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S (2003) The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Mol Cell Biol 23(6):1843–1855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chan MY, Huang H, Leung LK (2010) 2,3,7,8-Tetrachlorodibenzo-para-dioxin increases aromatase (CYP19) mRNA stability in MCF-7 cells. Mol Cell Endocrinol 317(1–2):8–13. doi:10.1016/j.mce.2009.11.012

    Article  CAS  PubMed  Google Scholar 

  5. Cheshenko K, Brion F, Le Page Y, Hinfray N, Pakdel F, Kah O, Segner H, Eggen RI (2007) Expression of zebra fish aromatase cyp19a and cyp19b genes in response to the ligands of estrogen receptor and aryl hydrocarbon receptor. Toxicol Sci 96(2):255–267. doi:10.1093/toxsci/kfm003

    Article  CAS  PubMed  Google Scholar 

  6. Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334. doi:10.1146/annurev.pharmtox.43.100901.135828

    Article  CAS  PubMed  Google Scholar 

  7. Dolwick KM, Schmidt JV, Carver LA, Swanson HI, Bradfield CA (1993) Cloning and expression of a human Ah receptor cDNA. Mol Pharmacol 44(5):911–917

    CAS  PubMed  Google Scholar 

  8. Mason ME, Okey AB (1982) Cytosolic and nuclear binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to the Ah receptor in extra-hepatic tissues of rats and mice. Eur J Biochem 123(1):209–215

    Article  CAS  PubMed  Google Scholar 

  9. Beischlag TV, Luis Morales J, Hollingshead BD, Perdew GH (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18(3):207–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Larsen MC, Angus WG, Brake PB, Eltom SE, Sukow KA, Jefcoate CR (1998) Characterization of CYP1B1 and CYP1A1 expression in human mammary epithelial cells: role of the aryl hydrocarbon receptor in polycyclic aromatic hydrocarbon metabolism. Cancer Res 58(11):2366–2374

    CAS  PubMed  Google Scholar 

  11. Ishida M, Mikami S, Kikuchi E, Kosaka T, Miyajima A, Nakagawa K, Mukai M, Okada Y, Oya M (2010) Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer. Carcinogenesis 31(2):287–295. doi:10.1093/carcin/bgp222

    Article  CAS  PubMed  Google Scholar 

  12. Chang JT, Chang H, Chen PH, Lin SL, Lin P (2007) Requirement of aryl hydrocarbon receptor overexpression for CYP1B1 up-regulation and cell growth in human lung adenocarcinomas. Clin Cancer Res 13(1):38–45. doi:10.1158/1078-0432.CCR-06-1166

    Article  CAS  PubMed  Google Scholar 

  13. Pesatori AC, Consonni D, Rubagotti M, Grillo P, Bertazzi PA (2009) Cancer incidence in the population exposed to dioxin after the “Seveso accident”: twenty years of follow-up. Environ Health 8:39. doi:10.1186/1476-069X-8-39

    Article  PubMed  PubMed Central  Google Scholar 

  14. Safe S, Wormke M, Samudio I (2000) Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells. J Mammary Gland Biol Neoplasia 5(3):295–306

    Article  CAS  PubMed  Google Scholar 

  15. Saito R, Miki Y, Hata S, Takagi K, Iida S, Oba Y, Ono K, Ishida T, Suzuki T, Ohuchi N, Sasano H (2014) Aryl hydrocarbon receptor in breast cancer-a newly defined prognostic marker. Horm Cancer 5(1):11–21. doi:10.1007/s12672-013-0160-z

    Article  CAS  PubMed  Google Scholar 

  16. Zhang S, Lei P, Liu X, Li X, Walker K, Kotha L, Rowlands C, Safe S (2009) The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr Relat Cancer 16(3):835–844. doi:10.1677/ERC-09-0054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sasano H, Anderson TJ, Silverberg SG, Santen RJ, Conway M, Edwards DP, Krause A, Bhatnagar AS, Evans DB, Miller WR (2005) The validation of new aromatase monoclonal antibodies for immunohistochemistry—a correlation with biochemical activities in 46 cases of breast cancer. J Steroid Biochem Mol Biol 95(1–5):35–39. doi:10.1016/j.jsbmb.2005.04.027

    Article  CAS  PubMed  Google Scholar 

  18. Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, Deb S (2005) Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57(3):359–383. doi:10.1124/pr.57.3.6

    Article  CAS  PubMed  Google Scholar 

  19. Lu M, Chen D, Lin Z, Reierstad S, Trauernicht AM, Boyer TG, Bulun SE (2006) BRCA1 negatively regulates the cancer-associated aromatase promoters I. 3 and II in breast adipose fibroblasts and malignant epithelial cells. J Clin Endocrinol Metab 91(11):4514–4519. doi:10.1210/jc.2006-1364

    Article  CAS  PubMed  Google Scholar 

  20. Lu D, Kiriyama Y, Lee KY, Giguere V (2001) Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors. Cancer Res 61(18):6755–6761

    CAS  PubMed  Google Scholar 

  21. Papoutsis AJ, Borg JL, Selmin OI, Romagnolo DF (2012) BRCA-1 promoter hypermethylation and silencing induced by the aromatic hydrocarbon receptor-ligand TCDD are prevented by resveratrol in MCF-7 cells. J Nutr Biochem 23(10):1324–1332. doi:10.1016/j.jnutbio.2011.08.001

    Article  CAS  PubMed  Google Scholar 

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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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Correspondence to Ryoko Saito.

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The authors declare that they do not have any conflict of interest.

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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

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