Journal of Biological Chemistry
Volume 282, Issue 13, 30 March 2007, Pages 10028-10035
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Molecular Basis of Cell and Developmental Biology
A Transgenic Model Reveals Important Roles for the NF-κB Alternative Pathway (p100/p52) in Mammary Development and Links to Tumorigenesis*

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A regulated pattern of nuclear factor κB (NF-κB) activation is essential for normal development of the mammary gland. An increase in NF-κB activity has been implicated in breast cancer. We have generated a novel transgenic mouse model to investigate the role of the alternative NF-κB pathway in ductal development and identify possible mediators of tumorigenesis downstream of p100/p52. By overexpressing the NF-κB p100/p52 subunit in mammary epithelium using the β-lactoglobulin milk protein promoter, we found that transgene expression resulted in increased overall NF-κB activity during late pregnancy. During pregnancy, p100/p52 expression resulted in delayed ductal development with impaired secondary branching and increased levels of Cyclin D1, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and cyclo-oxygenase-2 (COX-2) in the mammary gland. After multiple pregnancies the p100 transgenics exhibited a ductal thickening accompanied by small hyperplastic foci. In tumors from mice expressing the polyoma middle T oncoprotein (PyVT) in the mammary gland, increased levels of p100/p52 were present at the time of tumor development. These results show that increased p100/p52 disrupts normal ductal development and provides insight into the mechanism by which this may contribute to human breast cancer.

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This work was supported by grants from the Vanderbilt Ingram Cancer Center and by Susan G. Komen Foundation Grant BCTR02-1728. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement”in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.