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.
Brockdorff
B L
BL
Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark. blb@cancer.dk
Skouv
J
J
Reiter
B E
BE
Lykkesfeldt
A E
AE
D000970:Antineoplastic Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D015139:Blotting, Southern; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D018840:HSP70 Heat-Shock Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1