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 the metabolic activation of a number of procarcinogens and the hydroxylat ion of 17 beta-estradiol (E-2) at the C-2 and C-4 positions, respectiv ely. The aromatic hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlo rodibenzo-p-dioxin (TCDD) has a marked effect on estrogen metabolism i n MCF-7 breast-tumor cells by induction of these two enzymes. To inves tigate whether induction of CYP1A1 and CYP1B1 by AhR agonists and the associated increase in E-2 metabolism are common to all breast epithel ial cells and breast-tumor cells, we determined the effects of TCDD on E-2 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 MB-231 and MD A-MB-436) cell lines. In 184A1 cells, which did not express detectable estrogen receptor (ER) a mRNA, CYP1A1 mRNA and activity were induced by TCDD, and enhanced E-2 metabolism in TCDD-treated cells was predomi nantly E-2 2-hydroxylation. In MCF-10A, MCF-7, T-47D, ZR-75-1 and BT-2 0 cells, which expressed varying levels of ER alpha mRNA, both CYP1A1 and CYP1B1 mRNA levels and rates of both E-2 2- and 4-hydroxylation we re highly elevated following exposure to TCDD, In MIDA-MB157, MDA-MB-2 31 and MDA-MB-436 cells, which did not express detectable ER alpha mRN A and generally displayed fibroblastic or mesenchymal rather than epit helial morphology CYP1B1 induction was favored, and the rate of E-2 4- hydroxylation exceeded that of 2-hydroxylation in TCDD-treated cells, These results show that breast epithelial cells and tumor cells vary w idely with regard to AhR-mediated CYP1A1 and CYP1B1 induction, suggest ing that factors in addition to the AhR regulate CYP1A1 and CYP1B2 gen e expression, In these cell lines, significant CYP1A1 inducibility was restricted to cultures displaying epithelial morphology, whereas CYP1 B1 inducibility was observed in cells of both epithelial and mesenchym al morphology.