Compromised HOXA5 function can limit p53 expression in human breast tumours.
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.
Raman
V
V
Breast Cancer Program, Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Martensen
S A
SA
Reisman
D
D
Evron
E
E
Odenwald
W F
WF
Jaffee
E
E
Marks
J
J
Sukumar
S
S
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D016158:Genes, p53; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D004273:DNA, Neoplasm; C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; C059637:Hoxa5 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53