Nuclear factor-kappaB (NF-kappaB) regulates proliferation and branching in mouse mammary epithelium.
The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. Although recent studies have demonstrated aberrant expression or activity of NF-kappaB in human breast cancer cell lines and tumors, little is known regarding the precise role of NF-kappaB in normal proliferation and development of the mammary epithelium. We investigated the function of NF-kappaB during murine early postnatal mammary gland development by observing the consequences of increased NF-kappaB activity in mouse mammary epithelium lacking the gene encoding IkappaBalpha, a major inhibitor of NF-kappaB. Mammary tissue containing epithelium from inhibitor kappaBalpha (IkappaBalpha)-deficient female donors was transplanted into the gland-free mammary stroma of wild-type mice, resulting in an increase in lateral ductal branching and pervasive intraductal hyperplasia. A two- to threefold increase in epithelial cell number was observed in IkappaBalpha-deficient epithelium compared with controls. Epithelial cell proliferation was strikingly increased in IkappaBalpha-deficient epithelium, and no alteration in apoptosis was detected. The extracellular matrix adjacent to IkappaBalpha-deficient epithelium was reduced. Consistent with in vivo data, a fourfold increase in epithelial branching was also observed in purified IkappaBalpha-deficient primary epithelial cells in three-dimensional culture. These data demonstrate that NF-kappaB positively regulates mammary epithelial proliferation, branching, and functions in maintenance of normal epithelial architecture during early postnatal development.
Brantley
D M
DM
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2175, USA.
Chen
C L
CL
Muraoka
R S
RS
Bushdid
P B
PB
Bradberry
J L
JL
Kittrell
F
F
Medina
D
D
Matrisian
L M
LM
Kerr
L D
LD
Yull
F E
FE
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins; D020287:In Situ Nick-End Labeling; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019737:Transplants
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha