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Induction of insulin‐like growth factor binding protein expression by ICI 182,780 in a tamoxifen‐resistant human breast cancer cell line

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Abstract

Earlier studies in our laboratory demonstrated that the steroidal antiestrogen ICI 182,780 is very effective in abolishing the tamoxifen‐resistant proliferation of MCF 7/5‐23 cells [1]. In addition, preliminary binding studies showed that ICI 182,780 increased the binding of insulin‐like growth factor (IGF)‐I to the MCF 7/5‐23 cells, although this finding was not the result of an increase in the expression of the insulin‐like growth factor‐I receptor (IGF‐IR). Hence, we reasoned that the inhibition of tamoxifen‐resistant cell growth by ICI 182,780 might have been due to increased expression of insulin‐like growth factor binding proteins (IGFBPs).

We observed the up‐regulation of non‐insulin‐suppressible IGF‐I binding in both the tamoxifen‐sensitive MCF 7/5‐21 cell line (1.5‐fold) and the tamoxifen‐resistant MCF 7/5‐23 cell line (2.5‐fold) after 5 days of treatment with ICI 182,780 (10−7 M) in serum‐free medium, suggesting a role for cell‐associated IGFBPs. Affinity cross‐linking experiments confirmed the presence of an IGF‐I:IGFBP complex of approximately 38‐kDa in tamoxifen or ICI 182,780‐treated cells. Western ligand blots showed higher levels of a soluble 30‐kDa IGFBP in media conditioned by either of the subclones that had been treated with ICI 182,780, an effect consistently opposed by estrogen (E2:10−9 M). RT‐PCR showed higher levels of IGFBP‐5 mRNA than any of the other known IGFBPs, suggesting that this was the major IGFBP subtype. The protein was subsequently identified by Western immunoblotting as IGFBP‐5. In conclusion, we postulate that this may be a mechanism contributing to the greater potency of ICI 182,780 in the growth inhibition of the MCF 7/5‐23, tamoxifen‐resistant cell line.

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Authors and Affiliations

  1. Division of Haematology & Medical Oncology, Peter MacCallum Cancer Institute, Australia

    John P. Parisot, Xiu F. Hu & John R. Zalcberg

  2. Department of Medicine, University of Melbourne, Australia

    Kerri S. Leeding & Leon A. Bach

  3. Endocrinology & Metabolic Unit, Austin & Repatriation Medical Centre, Melbourne, Australia

    Mario DeLuise

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  1. John P. Parisot
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Parisot, J.P., Leeding, K.S., Hu, X.F. et al. Induction of insulin‐like growth factor binding protein expression by ICI 182,780 in a tamoxifen‐resistant human breast cancer cell line. Breast Cancer Res Treat 55, 231–242 (1999). https://doi.org/10.1023/A:1006274712664

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