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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    • "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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    • "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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