Increased expression of cytochrome p450 1A1 and 1B1 genes in anti-estrogen-resistant human breast cancer cell lines.

The expression of CYP1A1 and CYP1B1, encoding enzymes known to play a central role in oxidative metabolism of a wide range of compounds including steroids, was significantly increased in anti-estrogen-resistant human breast cancer cell lines. This was a purely regulatory phenomenon because no gene amplification had occurred. In anti-estrogen-sensitive MCF-7 cells, the steroidal anti-estrogen, ICI 182780, is able to induce the expression of the arylhydrocarbon receptor (AhR)-regulated gene product, CYP1A1, via an estrogen receptor (ER)- mediated process. This observation suggests cross-talk between the AhR and ER systems. Surprisingly, the increased constitutive expression in anti-estrogen-resistant cells of CYP1A1 and CYP1B1 mRNAs, encoding detoxification enzymes, had no effect on the activity of the ICI 182780 compound. The ICI 182780 regulation of estradiol-inducible genes was found to be identical in the resistant and sensitive breast cancer cell lines. In conclusion, anti-estrogen resistance is not due to conversion of ICI 182780 to less active compounds.