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

Dita Kleinman, Michael Karas, Michael Danilenko, Amit Arbeli, Charles Roberts, Derek LeRoith, Joseph Levy, Yoav Sharoni

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1089-1095
Number of pages7
JournalEndocrinology
Volume137
Issue number3
DOIs
StatePublished - 1996
Externally publishedYes

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Insulin-Like Growth Factor Binding Proteins
Tamoxifen
Endometrial Neoplasms
Insulin-Like Growth Factor I
Tyrosine
Phosphorylation
Growth
Somatomedins
Estradiol
IGF Type 1 Receptor
Estrogen Receptor Modulators
Estrogens
Breast Neoplasms
Insulin-Like Growth Factor Binding Protein 3
Membrane Proteins

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Kleinman, Dita; Karas, Michael; Danilenko, Michael; Arbeli, Amit; Roberts, Charles; LeRoith, Derek; Levy, Joseph; Sharoni, Yoav.

In: Endocrinology, Vol. 137, No. 3, 1996, p. 1089-1095.

Research output: Contribution to journalArticle

Kleinman, Dita ; Karas, Michael ; Danilenko, Michael ; Arbeli, Amit ; Roberts, Charles ; LeRoith, Derek ; Levy, Joseph ; Sharoni, Yoav. / 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. In: Endocrinology. 1996 ; Vol. 137, No. 3. pp. 1089-1095.
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