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

Autor: Scherbakov AM; Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia., Lobanova YS, Shatskaya VA, Onopchenko OV, Gershtein ES, Krasil'nikov MA
Jazyk: angličtina
Zdroj: Breast cancer research and treatment [Breast Cancer Res Treat] 2006 Nov; Vol. 100 (1), pp. 1-11. Date of Electronic Publication: 2006 Sep 20.
DOI: 10.1007/s10549-005-9075-x
Abstrakt: 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.
Databáze: MEDLINE
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