Aryl hydrocarbon receptor induced intratumoral aromatase in breast cancer
- 492 Downloads
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.
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.
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.
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.
KeywordsBreast cancer Aryl hydrocarbon receptor Aromatase Estrogen receptor pathway
Aryl hydrocarbon receptor
Breast cancer susceptibility gene 1
Fetal bovine serum
Invasive ductal carcinoma
Estrogen-inducible protein pS2
Ribosomal protein L13a
Tumor necrosis factor
We gratefully acknowledge Mr. Katsuhiko Ono and Erina Iwabuchi (Tohoku University School of Medicine) for providing excellent technical support.
Compliance with ethical statements
Conflict of interest
The authors declare that they do not have any conflict of interest.
- 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar