Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells

Human cytochromes P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) catalyze themetabolic activation of a number of procarcinogens and the hydroxylation of17beta-estradiol (E2) at the C-2 and C-4 positions, respectively. Thearomatic hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a marked effect on estrogenmetabolism in MCF-7 breast-tumor cells by induction of these two enzymes.To investigate whether induction of CYP1A1 and CYP1B1 by AhR agonists andthe associated increase in E2 metabolism are common to all breastepithelial cells and breast-tumor cells, we determined the effects of TCDDon E2 metabolism, and CYP1A1 and CYP1B1 mRNA levels in a series ofnon-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) celllines. In 184A1 cells, which did not express detectable estrogen receptor(ER) alpha mRNA, CYP1A1 mRNA and activity were induced by TCDD, andenhanced E2 metabolism in TCDD-treated cells was predominantly E22-hydroxylation. In MCF-10A, MCF-7, T-47D, ZR-75-1 and BT-20 cells, whichexpressed varying levels of ER alpha mRNA, both CYP1A1 and CYP1B1 mRNAlevels and rates of both E2 2- and 4- hydroxylation were highly elevatedfollowing exposure to TCDD. In MDA- MB-157, MDA-MB-231 and MDA-MB-436cells, which did not express detectable ER alpha mRNA and generallydisplayed fibroblastic or mesenchymal rather than epithelial morphology,CYP1B1 induction was favored, and the rate of E2 4-hydroxylation exceededthat of 2- hydroxylation in TCDD-treated cells. These results show thatbreast epithelial cells and tumor cells vary widely with regard to AhR-mediated CYP1A1 and CYP1B1 induction, suggesting that factors in additionto the AhR regulate CYP1A1 and CYP1B1 gene expression. In these cell lines,significant CYP1A1 inducibility was restricted to cultures displayingepithelial morphology, whereas CYP1B1 inducibility was observed in cells ofboth epithelial and mesenchymal morphology.