A transgenic model reveals important roles for the NF-kappa B alternative pathway (p100/p52) in mammary development and links to tumorigenesis.
A regulated pattern of nuclear factor kappaB (NF-kappaB) activation is essential for normal development of the mammary gland. An increase in NF-kappaB activity has been implicated in breast cancer. We have generated a novel transgenic mouse model to investigate the role of the alternative NF-kappaB pathway in ductal development and identify possible mediators of tumorigenesis downstream of p100/p52. By overexpressing the NF-kappaB p100/p52 subunit in mammary epithelium using the beta-lactoglobulin milk protein promoter, we found that transgene expression resulted in increased overall NF-kappaB 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.
Connelly
Linda
L
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232.
Robinson-Benion
Cheryl
C
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232.
Chont
Melissa
M
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232.
Saint-Jean
Leshana
L
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232.
Li
Haijing
H
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232.
Polosukhin
Vasiliy V
VV
Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650.
Blackwell
Timothy S
TS
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232; Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650.
Yull
Fiona E
FE
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232. Electronic address: yull@vanderbilt.edu.
D000818:Animals; D005260:Female; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development*; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology
D052003:NF-kappa B p52 Subunit