Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells.
Tamoxifen inhibited the oestrogen-stimulated proliferation of MCF-7 cells but had little effect on the oestrogen-stimulated proliferation of two tamoxifen-resistant variants (RL-3 and AL-1). The lack of oestrogen antagonist activity in the resistant cells was largely a result of an increased oestrogen agonist activity of tamoxifen on cell proliferation. Proliferation of the tamoxifen-resistant cells was also stimulated by 4-hydroxytamoxifen but not by ICI 164,384, a structurally distinct pure anti-oestrogen. Tamoxifen does not have increased oestrogen agonist activity for the induction of a series of oestrogen-regulated RNAs, and this suggests that the increased agonist activity may be restricted to key components involved in the proliferative response. Tamoxifen-stimulated cell proliferation was dependent on insulin-like growth factor I (IGF-1) in the resistant cells, suggesting that tamoxifen stimulates cell proliferation by sensitising cells to the proliferative effects of IGF-1. This may involve induction of the type-I IGF receptor.
Wiseman
L R
LR
Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, U.K.
Johnson
M D
MD
Wakeling
A E
AE
Lykkesfeldt
A E
AE
May
F E
FE
Westley
B R
BR
D001943:Breast Neoplasms / Q000188:drug therapy*; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D004967:Estrogens; D053284:Polyunsaturated Alkamides; D013629:Tamoxifen; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; C051781:ICI 164384; D017526:Receptor, IGF Type 1