Carcinogenesis, Vol 19, 291-298, Copyright © 1998 by Oxford University Press
DC Spink, BC Spink, JQ Cao, JA DePasquale, BT Pentecost, MJ Fasco, Y Li and TR Sutter
Human cytochromes P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) catalyze the
metabolic activation of a number of procarcinogens and the hydroxylation of
17beta-estradiol (E2) at the C-2 and C-4 positions, respectively. The
aromatic hydrocarbon receptor (AhR) agonist 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) has a marked effect on estrogen
metabolism in MCF-7 breast-tumor cells by induction of these two enzymes.
To investigate whether induction of CYP1A1 and CYP1B1 by AhR agonists and
the associated increase in E2 metabolism are common to all breast
epithelial cells and breast-tumor cells, we determined the effects of TCDD
on E2 metabolism, and CYP1A1 and CYP1B1 mRNA levels in a series of
non-tumor-derived breast epithelial (184A1 and MCF-10A) and breast-tumor
(MCF-7, T-47D, ZR-75-1, BT-20, MDA-MB-157, MDA-MB-231 and MDA-MB-436) cell
lines. In 184A1 cells, which did not express detectable estrogen receptor
(ER) alpha mRNA, CYP1A1 mRNA and activity were induced by TCDD, and
enhanced E2 metabolism in TCDD-treated cells was predominantly E2
2-hydroxylation. In MCF-10A, MCF-7, T-47D, ZR-75-1 and BT-20 cells, which
expressed varying levels of ER alpha mRNA, both CYP1A1 and CYP1B1 mRNA
levels and rates of both E2 2- and 4- hydroxylation were highly elevated
following exposure to TCDD. In MDA- MB-157, MDA-MB-231 and MDA-MB-436
cells, which did not express detectable ER alpha mRNA and generally
displayed fibroblastic or mesenchymal rather than epithelial morphology,
CYP1B1 induction was favored, and the rate of E2 4-hydroxylation exceeded
that of 2- hydroxylation in TCDD-treated cells. These results show that
breast epithelial cells and tumor cells vary widely with regard to AhR-
mediated CYP1A1 and CYP1B1 induction, suggesting that factors in addition
to the AhR regulate CYP1A1 and CYP1B1 gene expression. In these cell lines,
significant CYP1A1 inducibility was restricted to cultures displaying
epithelial morphology, whereas CYP1B1 inducibility was observed in cells of
both epithelial and mesenchymal morphology.
ARTICLES
Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells
Wadsworth Center, New York State Department of Health, Albany 12201- 0509, USA. david.spink@wadsworth.org
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