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      Compromised HOXA5 function can limit p53 expression in human breast tumours.

      Nature

      Animals, Apoptosis, Binding Sites, Breast Neoplasms, genetics, DNA, Neoplasm, metabolism, Gene Expression Regulation, Neoplastic, Genes, Homeobox, Genes, p53, Homeodomain Proteins, physiology, Humans, Mice, Phosphoproteins, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53

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          Abstract

          Expression of the p53 gene protects cells against malignant transformation. Whereas control of p53 degradation has been a subject of intense scrutiny, little is known about the factors that regulate p53 synthesis. 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 sites in the p53 promoterS. 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 gene, 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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          Journal
          10879542
          10.1038/35016125

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