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Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells

M Salerno1, D Sisci, L Mauro

  • 1Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

International Journal of Cancer
|April 3, 1999
PubMed

Insights

The antiestrogen ICI 182,780 inhibits breast cancer cell growth by reducing insulin receptor substrate 1 (IRS-1) expression and signaling. Overexpression of IRS-1 may lead to resistance to antiestrogen therapies.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Research

Background:

  • The pure antiestrogen ICI 182,780 inhibits proliferation in hormone-responsive breast cancer cells.
  • Interactions between ICI 182,780 and insulin-like growth factor-I receptor (IGF-IR) intracellular signaling are not well understood.

Purpose of the Study:

  • To investigate the effects of ICI 182,780 on IGF-IR signal transduction pathways in breast cancer cells.
  • To determine the role of insulin receptor substrate 1 (IRS-1) and src/collagen homology proteins (SHC) in mediating ICI 182,780's anti-proliferative effects.

Main Methods:

  • Studied ICI 182,780 effects on MCF-7 breast cancer cells and MCF-7-derived clones overexpressing IGF-IR, IRS-1, or SHC.
  • Assessed cell growth, protein expression, tyrosine phosphorylation, and protein-protein interactions (IRS-1/p85, IRS-1/GRB2, SHC/GRB2).

Main Results:

  • ICI 182,780 inhibited basal and IGF-I-induced growth in all cell lines, with IRS-1-overexpressing cells showing reduced sensitivity.
  • ICI 182,780 decreased IRS-1 expression and tyrosine phosphorylation, and reduced IRS-1/p85 and IRS-1/GRB2 binding in IRS-1-overexpressing cells.
  • ICI 182,780 suppressed IGF-I-induced IGF-IR tyrosine phosphorylation but did not significantly affect IGF-IR protein expression or SHC signaling.

Conclusions:

  • Downregulation of IRS-1 is a potential mechanism by which ICI 182,780 inhibits breast cancer cell growth.
  • Overexpression of IRS-1 in breast tumors may contribute to resistance to antiestrogen therapies.

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