Compromised HOXA5 Function Can Limit p53 Expression in Human Breast Tumours

Nature. 2000 Jun 22;405(6789):974-8. doi: 10.1038/35016125.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • DNA, Neoplasm
  • HOXA5 protein, human
  • Homeodomain Proteins
  • Hoxa5 protein, mouse
  • Phosphoproteins
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Protein p53