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Compromised HOXA5 function can limit p53 expression in human breast tumours

Nature volume 405, pages 974–978 (2000)Cite this article

Abstract

Expression of the p53 gene protects cells against malignant transformation1,2. Whereas control of p53 degradation has been a subject of intense scrutiny, little is known about the factors that regulate p53 synthesis1,2. Here we show that p53 messenger RNA levels are low in a large proportion of breast tumours. Seeking potential regulators of p53 transcription, we found consensus HOX binding sites3,4 in the p53 promoter5. Transient transfection of Hox/HOXA5 activated the p53 promoter. Expression of HOXA5 in epithelial cancer cells expressing wild-type p53, but not in isogenic variants lacking the p53 gene6, led to apoptotic cell death. Moreover, breast cancer cell lines and patient tumours display a coordinate loss of p53 and HOXA5 mRNA and protein expression. The HOXA5 promoter region was methylated in 16 out of 20 p53-negative breast tumour specimens. We conclude that loss of expression of p53 in human breast cancer may be primarily due to lack of expression of HOXA5.

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Figure 1: Human breast cancers express low levels of p53 and HOXA5 mRNA.
Figure 2: Mouse and human HOXA5 transactivate the p53 promoter.
Figure 3: HOXA5 upregulates p53 levels and initiates an apoptotic death pathway in breast cancer cells.
Figure 4: HOXA5 induces cell death in p53+/+ cells but not in p53-/- cells.
Figure 5: Loss of HOXA5 expression in breast cancer-gene silencing by methylation.

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Acknowledgements

This work was supported by grants from the USPHS, the Susan G. Komen Foundation, the Department of Defense and the Breast Cancer Research Foundation to S.S. We thank A. Rein and B. Vogelstein for discussions and for critically reviewing the manuscript, V. Band for generously sharing data and reagents, and D. Korz for expert technical assistance.

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Authors and Affiliations

  1. Breast Cancer Program, Johns Hopkins Oncology Center, Baltimore, 21231 , Maryland, USA

    Venu Raman, Shelby A. Martensen, Ella Evron, Elizabeth Jaffee & Saraswati Sukumar

  2. University of South Carolina, Columbia, 29208, South Carolina, USA

    David Reisman

  3. National Institutes of Health, Bethesda, 20892, Maryland, USA

    Ward F. Odenwald

  4. Duke University Medical Center, Durham, 27710, North Carolina, USA

    Jeffrey Marks

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  1. Venu Raman
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Correspondence to Saraswati Sukumar.

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Raman, V., Martensen, S., Reisman, D. et al. Compromised HOXA5 function can limit p53 expression in human breast tumours . Nature 405, 974–978 (2000). https://doi.org/10.1038/35016125

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