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Signaling and Regulation

Nuclear Factor-B Accounts for the Repressor Effects of High Stromal Cell-Derived Factor-1 Levels on Tac1 Expression in Nontumorigenic Breast Cells

¹Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey and ²Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey

^* To whom correspondence should be addressed. E-mail: rameshwa{at}umdnj.edu.

	Abstract

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that interacts with CXCR4 receptor. Tac1 encodes peptides belonging to the tachykinins, including substance P. SDF-1 production is decreased in Tac1 knockdown breast cancer cells and is also reduced in these cancer cells following contact with bone marrow stroma when Tac1 expression is increased. Here, we report on the effects of relatively high and low SDF-1 levels on Tac1 expression in nontumorigenic breast cells MCF12A. Reporter gene assays, Northern analyses, and ELISA for substance P showed increased Tac1 expression at 20 and 50 ng/mL SDF-1 and reduced expression at 100 ng/mL. Omission of the untranslated region showed a dose-dependent effect of SDF-1 on reporter gene activity, suggesting that receptor desensitization cannot account for the suppressive effects at 100 ng/mL SDF-1. Tac1 expression at high SDF-1 involves an intracellular signaling pathway that incorporates the activation of phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-AKT-nuclear factor-B (NF-B). The major repressive effect occurs via NF-B located within exon 1. In summary, NF-B is involved in the repression of Tac1 at higher levels of SDF-1 in MCF12A. These results are relevant to dysfunction of Tac1 in breast cancer cells and also provide insights on the behavior of breast cancer cells as they traverse across gradient changes of SDF-1. (Mol Cancer Res 2007;5(4):373-81)

Key Words: Tachykinins, SDF-1, NF-B, Bone marrow, Substance P, Breast cancer, Signal transduction, Mechanisms and signaling events, Promoter/enhancer analysis, Lymphokines, cytokines, chemokines, and growth factors

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