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12‐ O ‐tetradecanoylphorbol‐13‐acetate upregulates the Ah receptor and differentially alters CYP1B1 and CYP1A1 expression in MCF‐7 breast cancer cells
Author(s) -
Spink Barbara C.,
Fasco Michael J.,
Gierthy John F.,
Spink David C.
Publication year - 1998
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(19980901)70:3<289::aid-jcb1>3.0.co;2-j
Subject(s) - cyp1b1 , aryl hydrocarbon receptor , mcf 7 , cytochrome p450 , estrogen receptor , medicine , endocrinology , carcinogenesis , chemistry , hydroxylation , messenger rna , gene expression , receptor , aryl hydrocarbon receptor nuclear translocator , estrogen receptor alpha , biology , cancer research , cancer cell , cancer , breast cancer , metabolism , enzyme , biochemistry , gene , human breast , transcription factor
Elevated expression of cytochrome P450 1B1 (CYP1B1) and estradiol 4‐hydroxylation have been reported to be biomarkers of tumorigenesis in humans. The aromatic hydrocarbon receptor (AhR) regulates expression of human cytochrome P450 1A1 (CYP1A1) and CYP1B1, 17β‐estradiol (E 2 ) 2‐ and 4‐hydroxylases, respectively. There is also evidence that expression of estrogen receptor α (ERα) potentiates CYP1A1 inducibility in breast cancer cells. To characterize these relationships further, we examined the effects of 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA), which downregulates ERα, and the high‐affinity AhR ligand, 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD), on the expression of AhR, ERα, CYP1A1, and CYP1B1 in MCF‐7 human breast cancer cells. Treatment with TPA, which suppressed ERα mRNA levels, caused a greater than fourfold elevation of AhR mRNA and protein levels, whereas treatment with TCDD caused a decrease in AhR protein but no change in ERα or AhR mRNA levels. In MCF‐7 cells treated with TPA prior to treatment with TCDD, the AhR mRNA level was elevated, the ERα mRNA level remained suppressed, and the ratio of CYP1B1 to CYP1A1 mRNA was increased compared with treatment with TCDD alone. A corresponding increase in the ratio of the rates of 4‐ to 2‐hydroxylation pathways of E 2 metabolism was also observed in response to pretreatment with TPA prior to the addition of TCDD. These results demonstrate differential regulation of the human CYP1A1 and CYP1B1 genes and provide a cellular model to investigate further the mechanisms that may be involved in the elevated expression of CYP1B1 in tumorigenesis. J. Cell. Biochem. 70:289–296, 1998. © 1998 Wiley‐Liss, Inc.