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

Breast Cancer Res Treat. 2006 Nov;100(1):1-11. doi: 10.1007/s10549-005-9075-x. Epub 2006 Sep 20.


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 17beta-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-apoptotic machinery in the resistant breast cancer cells that forms independently of the acquired ability to estrogen-independent growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor / metabolism
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Selective Estrogen Receptor Modulators*
  • Signal Transduction
  • Tamoxifen*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism


  • Selective Estrogen Receptor Modulators
  • Vascular Endothelial Growth Factor A
  • Tamoxifen
  • ErbB Receptors