Regulation of insulin-like growth factor I receptor expression by the pure antiestrogen ICI 182780.
Insulin-like growth factor I (IGF-I) is a mitogen for human breast cancer cells both in vivo and in vitro. We demonstrate here that the antiestrogen ICI 182780 (ICI) at 10(-8) m decreases IGF-I receptor (IGF-IR) mRNA levels by 70% after treatment for 48 h. Measurements of mRNA stability indicate that the half-life of IGF-IR mRNA is approximately 3 h. Estradiol treatment increases the half-life of the IGF-IR mRNA to approximately 6 h and the level of IGF-IR gene transcription by 1.8-fold, whereas ICI treatment not only decreases the IGF-IR transcription rate by 50% but also decreases the IGF-IR mRNA half-life to less than 3 h. Affinity labeling studies with [125I]-IGF-I show 35% increased labeled IGF-I to MCF-7 cell membrane following estradiol treatment and 40% decreased labeling following ICI treatment. We also demonstrate that ICI attenuates IGF-I-stimulated growth. Our data suggest that attenuation of IGF-I responsivity by ICI may be due in part to reducing the IGF-IR expression.
Huynh
H
H
Lady Davis Research Institute, and Department of Medicine, McGill University, 3755 Cote St. Catherine Road, Montreal, Quebec H3T 1E2, Canada.
Nickerson
T
T
Pollak
M
M
Yang
X
X
D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000502:physiology; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006133:Growth Substances / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007457:Iodine Radioisotopes; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D004965:Estrogen Antagonists; D004967:Estrogens; D006133:Growth Substances; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1