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J. Biol. Chem., Vol. 282, Issue 13, 10028-10035, March 30, 2007

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A Transgenic Model Reveals Important Roles for the NF-B Alternative Pathway (p100/p52) in Mammary Development and Links to Tumorigenesis^*

Linda Connelly, Cheryl Robinson-Benion, Melissa Chont, Leshana Saint-Jean, Haijing Li, Vasiliy V. Polosukhin, Timothy S. Blackwell, and Fiona E. Yull¹

From the Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232 and the Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650

A regulated pattern of nuclear factor B (NF-B) activation is essential for normal development of the mammary gland. An increase in NF-B activity has been implicated in breast cancer. We have generated a novel transgenic mouse model to investigate the role of the alternative NF-B pathway in ductal development and identify possible mediators of tumorigenesis downstream of p100/p52. By overexpressing the NF-B p100/p52 subunit in mammary epithelium using the -lactoglobulin milk protein promoter, we found that transgene expression resulted in increased overall NF-B 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.

Received for publication, December 11, 2006 , and in revised form, January 19, 2007.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Cancer Biology, Vanderbilt University, 771 Preston Research Bldg., 2220 Pierce Ave., Nashville, TN 37232. Tel.: 615-343-2568; Fax: 615-936-2911; E-mail: Fiona. yull{at}vanderbilt.edu.

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