1: J Biol Chem. 2005 Jan 21;280(3):2294-9. Epub 2004 Nov 15. 

HOXA5-twist interaction alters p53 homeostasis in breast cancer cells.

Stasinopoulos IA, Mironchik Y, Raman A, Wildes F, Winnard P Jr, Raman V.

Department of Radiology, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205, USA.

The homeotic gene HOXA5 has been shown to play an important role in breast
tumorigenesis. We have shown that loss of p53 correlated with loss of a
developmentally regulated transcription factor, HOXA5, in primary breast cancer.
Searching for potential protein interacting partners we found that HOXA5 binds
to an anti-apoptotic protein, Twist. Furthermore, Twist-overexpressing MCF-7
cells displayed a deregulated p53 response to gamma-radiation and decreased
regulation of downstream target genes. Using a p53-promoter-reporter system, we
demonstrated that HOXA5 could partially restore the inhibitory effects of Twist
on p53 target genes. These effects are likely mediated through both the
transcriptional up-regulation of p53 and the protein-protein interaction between
HOXA5 and Twist. Thus, the loss of HOXA5 expression could lead to the functional
activation of Twist resulting in aberrant cell cycle regulation and promoting
breast carcinogenesis.

PMID: 15545268 [PubMed - indexed for MEDLINE]


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2: Mol Cell Biol. 2004 Jan;24(2):924-35. 

HOXA5-induced apoptosis in breast cancer cells is mediated by caspases 2 and 8.

Chen H, Chung S, Sukumar S.

Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns
Hopkins, 1650 Orleans Street, CRB 410, Baltimore, MD 21231-1000, USA.

HOXA5 is a transcriptional factor whose expression is lost in more than 60% of
breast carcinomas. Our previous work demonstrated that the overexpression of
HOXA5 in MCF7 cells resulted in cell death through a p53-dependent apoptotic
pathway. To determine whether p53-independent apoptotic pathways are involved in
HOXA5-induced cell death, we engineered a p53-mutant breast cancer cell line,
Hs578T, to inducibly express HOXA5. Induction of HOXA5 expression led to cell
death with features typical of apoptosis within 24 h, and the expression levels
of mutant p53 and its target genes either decreased or remained unchanged. To
decipher apoptotic pathways, the HOXA5-expressing cells were treated with a
variety of apoptotic inhibitors. Besides a general caspase inhibitor, caspase 2-
and 8-specific inhibitors largely abolished HOXA5-induced apoptosis, whereas
caspase 1-, 3-, 6-, and 9-specific inhibitors had no significant effects.
Western blot analysis further confirmed that caspases 2 and 8 were activated
after the induction of HOXA5 expression. Further, several small interfering RNAs
which specifically silenced caspase 2 and caspase 8 expression significantly
blocked HOXA5-induced apoptosis. HOXA5 expression could also sensitize cells to
tumor necrosis factor alpha-induced apoptosis by at least 100-fold. These
results indicate that expression of HOXA5 can induce apoptosis through an
apoptotic mechanism mediated by caspases 2 and 8.

PMID: 14701762 [PubMed - indexed for MEDLINE]


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3: Nature. 2000 Jun 22;405(6789):974-8. 

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

Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E, Marks J,
Sukumar S.

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

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.

PMID: 10879542 [PubMed - indexed for MEDLINE]


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