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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 volume 26, pages 3329–3337 (2007)Cite this article

Abstract

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, Δ133p53, 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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Acknowledgements

We thank Drs B Vogelstein, P Staller, M Kaplan, S Boswell and M Smith for various reagents. This work is supported by grants R01 CA89153, N01-CN-15133 (to HN), R01 HL67384 and R01 DK53674 (to HB) from the National Institutes of Health, American Institute for Cancer Research (03A069-REN) and Michael Guest Innovative Research Award from Walther Cancer Institute (to HN). HN is Marian J Morrison Investigator in Breast Cancer Research.

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Author notes

  1. K W Christopherson

    Present address: Institute of Molecular Medicine. The University of Texas Health Sciences Center, Houston, TX, USA

Authors and Affiliations

  1. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

    S A Mehta, R J Goulet Jr & H Nakshatri

  2. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    K W Christopherson & H E Broxmeyer

  3. Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA

    K W Christopherson, P Bhat-Nakshatri, H E Broxmeyer & H Nakshatri

  4. Walther Cancer Institute, Indianapolis, IN, USA

    K W Christopherson, P Bhat-Nakshatri, H E Broxmeyer & H Nakshatri

  5. CADRG, DCP, National Cancer Institute, Bethesda, MD, USA

    L Kopelovich

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Correspondence to H Nakshatri.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Mehta, S., Christopherson, K., Bhat-Nakshatri, P. 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 (2007). https://doi.org/10.1038/sj.onc.1210120

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