Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells.
The pure antiestrogen ICI 182,780 inhibits insulin-like growth factor (IGF)-dependent proliferation in hormone-responsive breast cancer cells. However, the interactions of ICI 182,780 with IGF-I receptor (IGF-IR) intracellular signaling have not been characterized. Here, we studied the effects of ICI 182,780 on IGF-IR signal transduction in MCF-7 breast cancer cells and in MCF-7-derived clones overexpressing either the IGF-IR or its 2 major substrates, insulin receptor substrate 1 (IRS-1) or src/collagen homology proteins (SHC). ICI 182,780 blocked the basal and IGF-I-induced growth in all studied cells in a dose-dependent manner; however, the clones with the greatest IRS-1 overexpression were clearly least sensitive to the drug. Pursuing ICI 182,780 interaction with IRS-1, we found that the antiestrogen reduced IRS-1 expression and tyrosine phosphorylation in several cell lines in the presence or absence of IGF-I. Moreover, in IRS-1-overexpressing cells, ICI 182,780 decreased IRS-1/p85 and IRS-1/GRB2 binding. The effects of ICI 182,780 on IGF-IR protein expression were not significant; however, the drug suppressed IGF-I-induced (but not basal) IGF-IR tyrosine phosphorylation. The expression and tyrosine phosphorylation of SHC as well as SHC/GRB binding were not influenced by ICI 182,780. In summary, downregulation of IRS-1 may represent one of the mechanisms by which ICI 182,780 inhibits the growth of breast cancer cells. Thus, overexpression of IRS-1 in breast tumors could contribute to the development of antiestrogen resistance.
Salerno
M
M
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Sisci
D
D
Mauro
L
L
Guvakova
M A
MA
Ando
S
S
Surmacz
E
E
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D018969:Insulin-Like Growth Factor Binding Proteins / Q000187:drug effects*; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011972:Receptor, Insulin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D000077267:Fulvestrant; D004958:Estradiol; D011972:Receptor, Insulin