title: Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction in IGF binding proteins.
abstract: A significant increase in endometrial cancer incidence in tamoxifen-treated breast cancer patients has been reported in many recent studies. The major growth stimulators of endometrial tumors are estrogens, but paradoxically, tamoxifen, a known antiestrogen, also stimulates their growth. The mode of action of estrogen can be partially explained by the modulation of insulin-like growth factor (IGF) autocrine or paracrine action. The purpose of the present study was to examine the involvement of the IGF system in the tamoxifen-stimulated growth of Ishikawa endometrial cancer cells by quantitating the IGF-I receptors and their phosphorylation, as well as membrane associated and secreted IGF-binding proteins (IGFBPs). Tamoxifen did not affect the number or affinity of IGF-I receptors. On the other hand, tamoxifen, similar to estradiol, increased IGF-I-stimulated tyrosine phosphorylation of cellular substrates. In contrast, in MCF-7 mammary cancer cells, tamoxifen reduced IGF-induced tyrosine phosphorylation in the presence of estradiol. The pure antiestrogen LY156758 did not affect Ishikawa basal cell growth but inhibited estradiol- and tamoxifen-induced growth. Growth inhibition by LY156758 of tamoxifen and estradiol-stimulated cells was accompanied by a corresponding inhibition of IGF-stimulated tyrosine phosphorylation. Tamoxifen caused a 3-fold decrease in membrane-associated IGFBPs. Moreover, a reduction in soluble IGFBPs was also observed, making the IGF peptides more available to the receptors. A parallel decrease in IGFBP-3 mRNA was also detected. These experiments suggest that tamoxifen, like estradiol, directly sensitizes endometrial cancer cells to the effects of IGFs that act through the type I receptor. Furthermore, the decrease in IGFBPs and the increase in tyrosine phosphorylation in the presence of tamoxifen provides a molecular mechanism that accounts for the uterotropic effects that are seen with tamoxifen therapy.
authors.affiliation: Clinical Biochemistry Department, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Kleinman
authors.forename: M
authors.initials: M
authors.lastname: Karas
authors.forename: M
authors.initials: M
authors.lastname: Danilenko
authors.forename: A
authors.initials: A
authors.lastname: Arbell
authors.forename: C T
authors.initials: CT
authors.lastname: Roberts
authors.forename: D
authors.initials: D
authors.lastname: LeRoith
authors.forename: J
authors.initials: J
authors.lastname: Levy
authors.forename: Y
authors.initials: Y
authors.lastname: Sharoni
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D020849:Raloxifene Hydrochloride; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013629:Tamoxifen / Q000009:adverse effects*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D018969:Insulin-Like Growth Factor Binding Proteins; D010880:Piperidines; D013629:Tamoxifen; D014443:Tyrosine; D020849:Raloxifene Hydrochloride; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1