NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression

Abstract

The transcription factor NF-κB 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-κB 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-β. We show here that the IKK-2/IκBα/NF-κB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-κB 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-β. Furthermore, inhibition of NF-κB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-κB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-κB 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-κB during distinct steps of breast cancer progression and suggest that the cooperation of Ras-and TGF-β-dependent signaling pathways in late-stage tumorigenesis depends critically on NF-κB activity. IntroductionCancer development and metastasis are multistep processes that involve local tumor growth and invasion followed by dissemination to and re-establishment at distant sites. The ability of a tumor to metastasize is the major determinant of the mortality of cancer patients. Thus, elucidating the molecular pathways essential for tumor metastasis is of high priority in cancer biology and provides a basis for novel therapeutic targets for the development of antimetastatic cancer treatments.Initially discovered and studied as a major activator of immune and inflammatory functions via its ability to induce expression of genes encoding cytokines, cytokine receptors, and cell-adhesion molecules, the transcription factor NF-κB has recently been implicated in the control of cell proliferation and oncogenesis (reviewed in ref. 1). NF-κB transcription factors bind to DNA as hetero-or homodimers that are composed of five possible subunits in mouse and human (RelA/p65, RelB, p50, and p52). These proteins are characterized by their Rel homology domains, which mediate DNA binding, dimerization, and interactions with inhibitory factors known as inhibitor κB (IκB) proteins. Whereas the Rel/p65 and p50 subunits are ubiquitously expressed, the p52, c-Rel, and RelB subunits are more functionally important in specific differentiated cell types (reviewed in ref.2). In most unstimulated cells, NF-κB dimers are inactive because of association with IκB proteins that mask the

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

“…As the enhanced expression of integrin a6b4 together with activation of RAS oncogene or inhibition of nuclear factor kappa B (NFkB) pathway will lead to development of invasive epidermal neoplasia (Dajee et al, 2003), we speculate this ability of DNp51B to induce integrin a6b4 is closely linked to its tumourigenic nature allowing continuous proliferation of neoplastic cells. As stated bellow a link between DNp51B and IKKa, which is a component of a canonical regulator of NFkB pathway (IKK signalosome), further strengthens close linkage of this pathway to the genesis of epidermal neoplasia and to epithelialmesenchymal transition adding invasiveness to neoplasia (Huber et al, 2004).…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…NF-κB regulates the process via its transcriptional activation of target genes, including VCAM-1, ICAM-1, MMPs and CXCR4 (Helbig et al, 2003). More importantly, IKKβ/IkBα/NF-κB pathway is required for the induction and maintenance of epithelial mesenchymal transition (EMT) in the mouse model (Huber et al, 2004). IKK-dependent but NF-κB transcription-independent function is also involved in the control of metastasis.…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…It should be noted that these studies often demonstrate that inhibition of NF-kB also causes reduction of tumor growth, so that it is difficult to demonstrate absolutely that NF-kB directly controls angiogenesis and metastasis. Finally, NF-kB has been shown to mediate the epithelial-mesenchymal transition (Huber et al, 2004a, b), although the exact mechanism is unclear.…”