NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4

Abstract

Metastasis of cancer cells is a complex process involving multiple steps including invasion, angiogenesis, and trafficking of cancer cells through blood vessels, extravasations, organ-specific homing, and growth. While matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines play a major role in invasion and angiogenesis, chemokines such as stromal derived factor-1␣ (SDF-1␣) and their receptors such as CXCR4 are thought to play a critical role in motility, homing, and proliferation of cancer cells at specific metastatic sites. We and others have previously reported that the extracellular signal-activated transcription factor NF-B up-regulates the expression of matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines in highly metastatic breast cancer cell lines. In this report, we demonstrate that NF-B regulates the motility of breast cancer cells by directly up-regulating the expression of CXCR4. Overexpression of the inhibitor of B (IB) in breast cancer cells with constitutive NF-B activity resulted in reduced expression of CXCR4 and a corresponding loss of SDF-1␣-mediated migration in vitro. Introduction of CXCR4 cDNA into IB-expressing cells restored SDF-1␣-mediated migration. Electrophoretic mobility shift assays and transient transfection assays revealed that the NF-B subunits p65 and p50 bind directly to sequences within the ؊66 to ؉7 region of the CXCR4 promoter and activate transcription. We also show that the cell surface expression of CXCR4 and the SDF-1␣-mediated migration are enhanced in breast cancer cells isolated from mammary fat pad xenografts compared with parental cells grown in culture. A further increase in CXCR4 cell surface expression and SDF-1␣-mediated migration was observed with cancer cells that metastasized to the lungs. Taken together, these results implicate NF-B in the migration and the organ-specific homing of metastatic breast cancer cells.Morbidity and mortality in cancer are mainly due to organspecific metastasis and the failure of chemotherapeutic drugs to selectively kill cancer cells at the sites of metastasis. Metastasis is a non-random process, and each cancer type has its own preferred sites of metastasis (1). For example, breast cancer cells preferentially metastasize to the regional lymph nodes, lungs, liver, and bone (1, 2). Prostate cancers usually metastasize to bone. While there has been considerable progress in identifying genes that promote the metastasis of cancer cells, little is known about the genes that enable cancer cells to seed, survive, and proliferate at sites of metastasis. Three models of organ-specific metastasis are currently under consideration: 1) selective survival and proliferation of cancer cells in a particular organ due to local production of appropriate growth factors, 2) organ-specific endothelial cells trapping circulating tumor cells by expressing appropriate adhesion molecules on their surface, and 3) organ-specific attractant molecules helping in homing cancer cells to specific sites (3). While...

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

“…Interestingly, CXCR4 has been shown to be regulated by NF-kB (Palkowitsch et al, 2008) and p53 (Mehta et al, 2007). Overexpression of DN-IkBa in breast cancer cells resulted in reduced expression of CXCR4, and a corresponding loss of SDF1a-mediated migration in vitro (Helbig et al, 2003). In view of all these observations and our earlier findings that ANXA1 expression is upregulated in metastatic cancer cells, we have shown that ANXA1 regulates CXCR4 in an NF-kB-dependent manner.…”

miR‐515‐5p controls cancer cell migration through MARK 4 regulation

“…MDA‐MB‐231 cells have previously been used to induce metastatic lesions in nude mice following inoculation into their mammary fat pads 19. Using samples from both primary and metastatic lesions obtained in these animals, we showed that miR‐515‐5p levels were down‐regulated in all metastatic lesions regardless of site (lung, bone, brain or adrenal glands) as compared to the corresponding primary tumour (Fig 6F, left panel).…”

“…MDA ‐ MB ‐231 cells were inoculated into the mammary fat pads of nude mice and allowed to form metastatic deposits 19. miR‐515‐5p and MARK 4 levels were then determined in the primary and indicated secondary lesions.…”

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).…”