The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells

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2005-05-01
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American English
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Oxford University Press
Abstract

Macrophage inhibitory cytokine 1 (MIC-1), a divergent member of the transforming growth factor beta superfamily, plays a role in the progression of a number of cancers, including breast, gastric, prostate and colorectal carcinomas. Serum MIC-1 levels are elevated in patients with metastatic prostate, breast and colorectal carcinomas. In vitro studies have revealed a cell type-specific role for MIC-1 in senescence and apoptosis. MIC-1 activates the survival kinase AKT/PKB in neuronal cells. Depending on the cell type, it activates or represses the MAP kinases ERK1/2. Mechanisms responsible for an increased MIC-1 expression in cancers and the consequences of MIC-1 overexpression, however, are not known. In this study, we show that AKT/PKB directly regulates the expression of MIC-1 in breast cancer cells. Sequences within −88 to +30 of the MIC-1 promoter are required for the AKT-mediated induction of MIC-1. This region of the promoter contains two SP-1 binding sites (SP-1B and SP-1C), which bind to the SP-1 and SP-3 proteins. Mutation of SP-1C but not SP-1B reduced the AKT-mediated activation of MIC-1. MIC-1 increased the basal ERK1 phosphorylation and prolonged the estrogen-stimulated ERK1 phosphorylation in MCF-7 breast cancer cells without altering the phosphorylation status of AKT/PKB. Immunohistochemistry with MIC-1 antibody revealed an MIC-1 expression within the cancer cells of primary breast cancer and in the MCF-7 xenografts. Furthermore, a limited analysis of RNA from primary breast cancers revealed an overexpression of MIC-1 in tumors, compared with normal tissues. These results suggest that AKT/PKB through MIC-1 could regulate the ERK1 activity and the MIC-1 expression levels may serve as a surrogate marker for the AKT activation in tumors.

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Wollmann, W., Goodman, M. L., Bhat-Nakshatri, P., Kishimoto, H., Goulet, R. J., Mehrotra, S., … Nakshatri, H. (2005). The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells. Carcinogenesis, 26(5), 900–907. https://doi.org/10.1093/carcin/bgi031
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0143-3334
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