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

Abstract 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.