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Activation of mitogenic pathways and sensitization to estrogen-induced apoptosis: two independent characteristics of tamoxifen-resistant breast cancer cells?

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Summary

Paradoxical induction of apoptosis by estrogen has been described previously for estrogen-deprived and antiestrogen-resistant breast cancer cells. In this study we analyzed the possible interrelations between cell sensitization to estrogen apoptotic action and cell ability to (anti)estrogen-independent growth. Using tamoxifen-resistant sublines derived from the parent MCF-7 breast cancer cells by long-term tamoxifen treatment we demonstrated that resistant cells are characterized by increased level of EGF receptor and unexpected increase of VEGF receptor 2 (Flk-1/KDR) and its specific ligand, VEGF-A. The importance of the VEGF signaling in the autocrine regulation of cell growth was indicated by the ability of VEGF inhibitor, soluble fragment of Flt-1/Fc chimera, to suppress the phosphorylation of MAP kinases as well as to inhibit the estrogen-independent growth of MCF-7 cells. Sensitization of tamoxifen-resistant cells to estrogen-induced apoptosis required the additional continuous cultivation in steroid-depleted medium and did not depend on the activity of both EGF and VEGF pathways. Finally, we showed that treatment of the cells with 17β-estradiol (10−9 M) resulted in a marked increase in p53 level both in the resistant cells undergoing apoptosis and in the parent MCF-7 cells insensitive to apoptotic estrogen action. These data provide an important support for the existence of a disbalance between pro- and anti-apoptotiс machinery in the resistant breast cancer cells that forms independently of the acquired ability to estrogen-independent growth.

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Abbreviations

DCC:

dextran-coated charcoal

ER:

estrogen receptor

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

FBS:

fetal bovine serum

IGF-1:

insulin-like growth factor

MAP kinases:

mitogen-activated protein kinase

PBS:

phosphate-buffered saline

PKB:

protein kinase B

PI3K:

phosphatidylinositol-3-OH kinase

SD:

standard deviation value

sFlt-1/Fc:

soluble fragment of Flt-1/Fc chimera

VEGF (VEGF-A):

vascular endothelial growth factor A

VEGFR:

vascular endothelial growth factor receptor

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Acknowledgements

This work was supported in part by Russian Foundation for Basic Research, grants 04-04-48458 and 03-03-32111. We thank Olga Burova (Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia) for assistance in FACS analysis.

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Authors and Affiliations

  1. Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia

    Alexander M. Scherbakov & Elena S. Gershtein

  2. Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia

    Yulia S. Lobanova, Valentina A. Shatskaya, Oksana V. Onopchenko & Mikhail A. Krasil’nikov

  3. Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia

    Mikhail A. Krasil’nikov

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  1. Alexander M. Scherbakov
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  2. Yulia S. Lobanova
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  4. Oksana V. Onopchenko
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  5. Elena S. Gershtein
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Correspondence to Mikhail A. Krasil’nikov.

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Scherbakov, A.M., Lobanova, Y.S., Shatskaya, V.A. et al. Activation of mitogenic pathways and sensitization to estrogen-induced apoptosis: two independent characteristics of tamoxifen-resistant breast cancer cells?. Breast Cancer Res Treat 100, 1–11 (2006). https://doi.org/10.1007/s10549-005-9075-x

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  • DOI: https://doi.org/10.1007/s10549-005-9075-x

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