Activation of mitogenic pathways and sensitization to estrogen-induced apoptosis: two independent characteristics of tamoxifen-resistant breast cancer cells?
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.
Scherbakov
Alexander M
AM
Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia.
Lobanova
Yulia S
YS
Shatskaya
Valentina A
VA
Onopchenko
Oksana V
OV
Gershtein
Elena S
ES
Krasil'nikov
Mikhail A
MA
D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020845:Selective Estrogen Receptor Modulators; D015398:Signal Transduction; D013629:Tamoxifen; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D020845:Selective Estrogen Receptor Modulators; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D066246:ErbB Receptors