NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression.
The transcription factor NF-kappaB is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-kappaB in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-beta. We show here that the IKK-2/IkappaBalpha/NF-kappaB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-kappaB signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-beta. Furthermore, inhibition of NF-kappaB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-kappaB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-kappaB activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-kappaB during distinct steps of breast cancer progression and suggest that the cooperation of Ras- and TGF-beta-dependent signaling pathways in late-stage tumorigenesis depends critically on NF-kappaB activity.
Huber
Margit A
MA
Department of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.
Azoitei
Ninel
N
Baumann
Bernd
B
Grünert
Stefan
S
Sommer
Andreas
A
Pehamberger
Hubert
H
Kraut
Norbert
N
Beug
Hartmut
H
Wirth
Thomas
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002472:Cell Transformation, Viral; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D015689:Oncogene Protein p21(ras)