The breast cancer cells response to chronic hypoxia involves the opposite regulation of NF-kB and estrogen receptor signaling |
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Authors: | Alexander M Scherbakov Valentina A Shatskaya |
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Institution: | a Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, Russian N.N. Blokhin Cancer Research Centre, Kashirskoye shosse 24, Moscow 115478, Russia b Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre, Kashirskoye shosse 24, Moscow 115478, Russia |
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Abstract: | The progression of cancer is associated with tumor's ability to outgrow the existing vasculature resulting in chronic hypoxic pressure, however the molecular mechanism of cancer cell response to chronic hypoxia is poorly understood. In this study we have analyzed the reorganization of estrogen receptor (ER) signaling in breast cancer cells under chronic hypoxia and examined the role of interrelations between ER and NF-kB signaling in cell adaptation to hypoxia. Using long-term culturing of MCF-7 breast cancer cells in hypoxia-mimetic conditions (cobalt chloride) we have established a hypoxia-tolerant subline characterized by HIF-1 hyperexpression that retained the tolerance to hypoxia even when the cells were returned to normoxic conditions.The hypoxia-tolerant cells were characterized by non-affected ER signaling, irreversible suppression of NF-kB activity, and increased sensitivity to cytokine-induced apoptosis. Estradiol treatment suppressed the NF-kB activity in both parent and hypoxia-tolerant MCF-7 cells. In contrast to MCF-7 cells, the exposure of estrogen-independent MCF-7/T2 subline to chronic hypoxia was not accompanied by noticeable changes in NF-kB activity or cell sensitivity to cytokines. Taken together, the results presented demonstrate the importance of interrelations between ER and NF-kB signaling in the response of estrogen-dependent breast cancer cells to chronic hypoxia. |
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Keywords: | NF-kB Hypoxia Estrogen Estrogen receptor MCF-7 Breast cancer |
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