Nuclear factor-kappaB enhances ErbB2-induced mammary tumorigenesis and neoangiogenesis in vivo.
The (HER2/Neu) ErbB2 oncogene is commonly overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in transgenic mice. Nuclear factor (NF)-kappaB activity is increased in both human and murine breast tumors. The immune response to mammary tumorigenesis may regulate tumor progression. The role of endogenous mammary epithelial cell NF-kappaB had not previously been determined in immune-competent animals. Furthermore, the role of the NF-kappaB components, p50 and p65, in tumor growth was not known. Herein, the expression of a stabilized form of the NF-kappaB-inhibiting IkappaBalpha protein (IkappaBalphaSR) in breast tumor cell lines that express oncogenic ErbB2 inhibited DNA synthesis and growth in both two- and three-dimensional cultures. Either NF-kappaB inhibition or selective silencing of p50 or p65 led to a loss of contact-independent tumor growth in vitro. IkappaBalphaSR reversed the features of the oncogene-induced phenotype under three-dimensional growth conditions. The NF-kappaB blockade inhibited ErbB2-induced mammary tumor growth in both immune-competent and immune-deficient mice. These findings were associated with both reduced tumor microvascular density and a reduction in the amount of vascular endothelial growth factor. The expression of IkappaBalphaSR in breast cancer tumors inhibited angiogenesis. Thus, mammary epithelial cell NF-kappaB activity enhances ErbB2-mediated mammary tumorigenesis in vivo by promoting both growth and survival signaling via the promotion of tumor vasculogenesis.
Liu
Manran
M
Department of Cancer Biology, Kimmel Cancer Center,Jefferson Stem Cell and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Ju
Xiaoming
X
Willmarth
Nicole E
NE
Casimiro
Mathew C
MC
Ojeifo
John
J
Sakamaki
Toshiyuki
T
Katiyar
Sanjay
S
Jiao
Xuanmao
X
Popov
Vladimir M
VM
Yu
Zuoren
Z
Wu
Kongming
K
Joyce
David
D
Wang
Chenguang
C
Pestell
Richard G
RG
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D015674:Mammary Neoplasms, Animal / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D034741:RNA, Small Interfering / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse