Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased IGF-induced tyrosine phosphorylation and reduction in IGFBPs

Clinical Biochemistry Department, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Endocrinology (Impact Factor: 4.5). 04/1996; 137(3):1089-95. DOI: 10.1210/en.137.3.1089
Source: PubMed


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.

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    • "We found that the functions of protein phosphorylation in all the enriched KEGG pathways are supported by previous studies. Table 2 Enriched KEGG pathways for selected human proteins KEGG ID P value KEGG Term References 04110 0.000 Cell cycle Bradbury et al., 1974; Lee et al., 1988; Atherton-Fessler et al., 1993; Lew and Kornbluth, 1996; Matsuoka et al., 1998; Konishi et al., 2002; Yu and Chen, 2004 05215 0.000 Prostate cancer Haldar et al., 1996; Lin et al., 2002; El Sheikh et al., 2004; Jiang et al., 2004; Kreisberg et al., 2004; Jaggi et al., 2005; Chen et al., 2006; Shimada et al., 2006; Mahajan et al., 2007; Bianchini et al., 2008 04520 0.000 Adherens junction Volberg et al., 1992; Collares-Buzato et al., 1998; Andriopoulou et al., 1999; Gomez et al., 1999; Tinsley et al., 1999; Serres et al., 2000; Shasby et al., 2002 04910 0.000 Insulin signaling pathway Myers et al., 1998; Zick, 2001; Aguirre et al., 2002; Andreozzi et al., 2004; Ueki et al., 2004; Gual et al., 2005; McManus et al., 2005; Ueno et al., 2005; D'Alessandris et al., 2007; Wang et al., 2007 03013 0.000 RNA transport Aubol et al., 2004; Topisirovic et al., 2004 03040 0.000 Spliceosome Mermoud et al., 1994; Wang et al., 1999; Mathew et al., 2008 05200 0.000 Pathways in cancer Foster and Wimalasena, 1996; Itoh et al., 2002; Viglietto et al., 2002; Vivanco and Sawyers, 2002; Altomare et al., 2004; Viatour et al., 2005; Cicenas, 2008 05213 0.000 Endometrial cancer Kleinman et al., 1996; Kanamori et al., 2001; Terakawa et al., 2003 05220 0.000 Chronic myeloid leukemia Oda et al., 1996; Coluccia et al., 2007; Jilani et al., 2008; Jalkanen et al., 2011; Zhang et al., 2012 04810 0.000 Regulation of actin cytoskeleton Arber et al., 1998; Sumi et al., 1999; Head et al., 2003; Vardouli et al., 2005; Park et al., 2012 04114 0.000 Oocyte meiosis Dekel, 1996; Fan et al., 2002; Wang et al., 2006a; Liang et al., 2007; Swain and Smith, 2007 05223 0.000 Non-small cell lung cancer Lee et al., 2002; Cappuzzo et al., 2004; Kim et al., 2005; Tang et al., 2006; Tsurutani et al., 2006 "
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    • "Tamoxifen caused a 3-fold decrease in IGF BPs. Moreover, a reduction in soluble IGF BPs was also observed, making the IGF peptides more available to the receptors [46]. "
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    • "Cells were incubated for 3 days with or without the different stimuli as described in the figure legends. As an indirect measure of growth, the 3-[4,5-dimethylthiazol 2-yl] 2,5-diphenyltetrazolium bromide (MTT) assay was used as previously described [18]. "
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