Mehta SA, Christopherson KW, Bhat-Nakshatri P, Goulet Jr RJ, Broxmeyer HE, Kopelovich L et al.. Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion. Oncogene 26: 3329-3337

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Oncogene (Impact Factor: 8.46). 06/2007; 26(23):3329-37. DOI: 10.1038/sj.onc.1210120
Source: PubMed


Chemokine receptor CXCR4 and its ligand CXCL12 are suggested to be involved in migration, invasion and metastasis of breast cancer cells. Mutation of the tumor suppressor gene p53 in breast cancer is associated with metastasis and aggressive clinical phenotype. In this report, we demonstrate that wild type but not the dominant-negative mutant (V143A) or cancer-specific mutants (R175H or R280K) of p53 repress CXCR4 expression. Recently described cancer-specific p53 isoform, Delta133p53, also failed to repress CXCR4 promoter activity. Short-interfering RNA-mediated depletion of p53 increased endogenous CXCR4 expression in MCF-7 breast cancer cells that contain wild-type p53. Basal CXCR4 promoter activity in HCT116 colon carcinoma cells deleted of p53 [HCT116(p53KO)] was 10-fold higher compared to that in parental HCT116 cells with functional wild-type p53. Deletion analysis of CXCR4 promoter identified a seven-base pair p53-repressor element homologous to cyclic AMP/AP-1 response (CRE/AP-1) element. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed binding of ATF-1 and cJun to the CRE/AP-1 element. The p53 rescue drug PRIMA-1 reduced CXCR4 mRNA and cell surface expression in MDA-MB-231 cells, which express R280K mutant p53. CP-31398, another p53 rescue drug, similarly reduced cell surface levels of CXCR4. PRIMA-1-mediated decrease in CXCR4 expression correlated with reduced invasion of MDA-MB-231 cells through matrigel. These results suggest a mechanism for elevated CXCR4 expression and metastasis of breast cancers with p53 mutations or isoform expression. We propose that p53 rescue drugs either alone or in combination with chemotherapeutic drugs may be effective in reducing CXCR4-mediated metastasis.

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    • "Among those genes pro-proliferative and anti-apoptotic molecules were down-regulated – such as IGF1 and LTF which act through regulation of the AKT signaling pathway[27] and ERK1/2 pathway[28] respectively. PRIMA1 modulates CXCR4 expression[29] – a molecule that already has been described to correlate strongly with increased lymphatic metastasis[11], [12], [29]. "
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    ABSTRACT: Lymph node metastasis indicates poor prognosis in esophageal cancer. To understand the underlying mechanisms, most studies so far focused on investigating the tumors themselves and/or invaded lymph nodes. However they neglected the potential events within the metastatic niche, which precede invasion. Here we report the first description of these regulations in patients on transcription level. We determined transcriptomic profiles of still metastasis-free regional lymph nodes for two patient groups: patients classified as pN1 (n = 9, metastatic nodes exist) or pN0 (n = 5, no metastatic nodes exist). All investigated lymph nodes, also those from pN1 patients, were still metastasis-free. The results show that regional lymph nodes of pN1 patients differ decisively from those of pN0 patients - even before metastasis has taken place. In the pN0 group distinct immune response patterns were observed. In contrast, lymph nodes of the pN1 group exhibited a clear profile of reduced immune response and reduced proliferation, but increased apoptosis, enhanced hypoplasia and morphological conversion processes. DKK1 was the most significant gene associated with the molecular mechanisms taking place in lymph nodes of patients suffering from metastasis (pN1). We assume that the two molecular profiles observed constitute different stages of a progressive disease. Finally we suggest that DKK1 might play an important role within the mechanisms leading to lymph node metastasis.
    PLoS ONE 07/2014; 9(7):e102552. DOI:10.1371/journal.pone.0102552 · 3.23 Impact Factor
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    • "Because MMP1 is a target gene for wild-type p53 activity, the functional inactivation of the protein results in a gene overexpression that allows tumor cell migration after degradation of basement membrane and cell detachment [30, 31]. The concomitant overexpression of CXCR4 due to a gain-of-function mutant p53 [32, 33], further contributes to enhance tumor cell migration and metastatic spread [34]. In fact, CXCR4 encodes a C-X-C motif chemokine receptor specific for stromal cell-derived factor-1 (SDF-1/CXCL12), a member of the family of chemoattractant molecules, physiologically involved in the migration of immune cells. "
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    ABSTRACT: Altered p53 protein is prevalently associated with the pathologic class of triple-negative breast cancers and loss of p53 function has recently been linked to the induction of an epithelial-mesenchymal transition (EMT) and acquisition of stemness properties. We explored the association between TP53 mutational status and expression of some genes involved in the canonical TGF-β signaling pathway (the most potent EMT inducer) and in two early EMT associated events: loss of cell polarity and acquisition of stemness-associated features. We used a publicly accessible microarray dataset consisting of 251 p53-sequenced primary breast cancers. Statistical analysis indicated that mutant p53 tumors (especially those harboring a severe mutation) were consistent with the aggressive class of triple-negative cancers and that, differently from cell cultures, surgical tumors underexpressed some TGF-β related transcription factors known as involved in EMT (ID1, ID4, SMAD3, SMAD4, SMAD5, ZEB1). These unexpected findings suggest an interesting relationship between p53 mutation, mammary cell dedifferentiation, and the concomitant acquisition of stemlike properties (as indicated by the overexpression of PROM1 and NOTCH1 genes), which improve tumor cells aggressiveness as indicated by the overexpression of genes associated with cell proliferation (CDK4, CDK6, MKI67) and migration (CXCR4, MMP1).
    BioMed Research International 07/2012; 2012:254085. DOI:10.1155/2012/254085 · 2.71 Impact Factor
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    • "CXCR4 expression increases progressively with increasing malignant potential, and higher expression is associated with lymph node positivity, hormone receptor negativity, Her2 overexpression and poor survival in breast cancer (Cabioglu et al., 2005; Mehta et al., 2007), and that CXCR4 can act as a biomarker for metastasis (Cabioglu et al., 2005). 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). "
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    ABSTRACT: The molecular mechanisms underlying constitutive nuclear factor-κB (NF-κB) activation in solid tumors has not been elucidated. We show that Annexin-1 (ANXA1) is involved in this process, and suppression of ANXA1 in highly metastatic breast cancer cells impedes migration and metastasis capabilities in vitro and in vivo. ANXA1 expression correlates with NF-κB activity, suggesting that ANXA1 may be required for the constitutive activity of IκB kinase (IKK) and NF-κB in highly metatstatic breast cancer. Gel-filtration analysis demonstrated that ANXA1 co-elutes with the members of the IKK complex and NF-κB signaling pathway, and immunoprecipitation confirmed that ANXA1 can bind to and interact with IKKγ or NEMO, but not IKKα or IKKβ. Importantly, silencing of ANXA1 prevents the interaction of NEMO and RIP1, which indicates that ANXA1 is required for the recruitment of RIP1 to the IKK complex, which may be important for the activation of NF-κB. Downstream targets of NF-κB include uPA and CXCR4, which can be modulated by ANXA1 silencing. CXCR4-mediated migration of breast cancer cell lines in response to CXCL12 was significantly modulated by ANXA1, indicating its importance in the tissue-specific migration of breast cancer cells. Chromatin immunoprecipitation experiments confirmed that in ANXA1 overexpressed cells, NF-κB was recruited to CXCR4 promoter without external stimulation, indicating that ANXA1 is critical for the constitutive activation of NF-κB in breast cancer to promote metastasis. Finally, we show that ANXA1 overexpression enhances metastasis and reduces survival in an intracardiac metastasis model, while ANXA1-deficient mice crossed with MMTV-PyMT mice display significantly less metastasis than their heterozygous littermates, indicating that ANXA1 is an important gene in breast cancer metastasis. Our data reveal that ANXA1 can constitutively activate NF-κB in breast cancer cells through the interaction with the IKK complex, and suggests that modulating ANXA1 levels has therapeutic potential to suppress breast cancer metastasis.
    Oncogene 03/2011; 30(28):3174-85. DOI:10.1038/onc.2011.28 · 8.46 Impact Factor
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