Components of the IGF system mediate the opposing effects of tamoxifen on endometrial and breast cancer cell growth.
The involvement of the IGF system in the growth regulation of hormone-dependent (e.g. endometrial and breast) cancer cells was studied. We chose two opposing effects of tamoxifen: the paradoxical stimulation of Ishikawa endometrial cancer cells growth and its inhibitory effect on MCF-7 mammary cancer cells. The results clearly confirm our working hypothesis that the IGF system is involved in growth regulation of these cancer cells irrespective of the direction of the drug effect. The following parameters of the IGFs system were studied: IGF-I receptors, IGF-I stimulated protein tyrosine phosphorylation, and membrane-associated and secreted IGF-binding proteins (IGFBPs). In Ishikawa cells, tamoxifen, similar to estradiol, increased IGF-I stimulated tyrosine phosphorylation of cellular substrates in accordance with its effect on cell growth. This effect of tamoxifen was inverted in MCF-7 cells. Tamoxifen did not affect the number or affinity of IGF-I receptors in both Ishikawa and MCF-7 cells, however, it caused a three-fold decrease in membrane-associated IGFBPs in the endometrial cells but an increase in these proteins in breast cancer cells. Similar but much less pronounced changes in soluble IGFBPs were observed. Our results indicate that the opposing growth effects of tamoxifen an endometrial and mammary cancer cells are associated with modulation of the IGF system components, mainly with reciprocal changes in membrane-associated IGFBPs.
Karas
M
M
Clinical Biochemistry Department, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.
Kleinman
D
D
Danilenko
M
M
Roberts
C T
CT
LeRoith
D
D
Levy
J
J
Sharoni
Y
Y
D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013002:Somatomedins / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018969:Insulin-Like Growth Factor Binding Proteins; D013002:Somatomedins; D013629:Tamoxifen; D004958:Estradiol; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1