Compromised HOXA5 function can limit p53 expression in human breast tumours

Venu Raman, Shelby A. Martensen, David Reisman, Ella Evron, Ward F. Odenwald, Elizabeth Jaffee, Jeffrey Marks and Saraswati Sukumar ()
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Venu Raman: Breast Cancer Program, Johns Hopkins Oncology Center
Shelby A. Martensen: Breast Cancer Program, Johns Hopkins Oncology Center
David Reisman: University of South Carolina
Ella Evron: Breast Cancer Program, Johns Hopkins Oncology Center
Ward F. Odenwald: National Institutes of Health
Elizabeth Jaffee: Breast Cancer Program, Johns Hopkins Oncology Center
Jeffrey Marks: Duke University Medical Center
Saraswati Sukumar: Breast Cancer Program, Johns Hopkins Oncology Center

Nature, 2000, vol. 405, issue 6789, 974-978

Abstract: 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.

Date: 2000
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DOI: 10.1038/35016125

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