Carcinogenesis Advance Access published online on January 27, 2005
Carcinogenesis, doi:10.1093/carcin/bgi031
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1 Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
* To whom correspondence should be addressed. Macrophage inhibitory cytokine 1 (MIC-1), a divergent member of the transforming growth factor beta superfamily, plays a role in progression of 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 cell type specific role for MIC-1 in senescence and apoptosis. MIC-1 activates the survival kinase AKT/PKB in neuronal cells. Depending on cell type, it activates or represses MAP kinases ERK1/2. Mechanisms responsible for increased MIC-1 expression in cancers and 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 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 SP-1 and SP-3 proteins. Mutation of SP-1C but not SP-1B reduced AKT-mediated activation of MIC-1. MIC-1 increased basal ERK1 phosphorylation and prolonged estrogen-stimulated ERK1 phosphorylation in MCF-7 breast cancer cells without altering the phosphorylation status of AKT/PKB. Immunohistochemistry with MIC-1 antibody revealed MIC-1 expression within cancer cells of primary breast cancer and in MCF-7 xenografts. Furthermore, a limited analysis of RNA from primary breast cancers revealed overexpression of MIC-1 in tumors compared to normal tissues. These results suggest that AKT/PKB through MIC-1 can regulate ERK1 activity and MIC-1 expression levels may serve as a surrogate marker for AKT activation in tumors.
Received September 1, 2004
Revised January 10, 2005
Accepted January 18, 2005
CANCER BIOLOGY
The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells
2 Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Walther Cancer Institute, Indianapolis, Indiana 46208, USA
3 Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
4 Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; Walther Cancer Institute, Indianapolis, Indiana 46208, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
Harikrishna Nakshatri, E-mail: hnakshat{at}iupui.edu
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