Expression of full-length p53 and its isoform Δp53 in breast carcinomas in relation to mutation status and clinical parameters

doi:10.1186/1476-4598-5-47

Molecular Cancer

Volume 5

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Baumbusch LO
Myhre S
Langerød A
Bergamaschi A
Geisler SB
Lønning PE
Deppert W
Dornreiter I
Børresen-Dale AL

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Baumbusch LO
Myhre S
Langerød A
Bergamaschi A
Geisler SB
Lønning PE
Deppert W
Dornreiter I
Børresen-Dale AL
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Research

Expression of full-length p53 and its isoform Δp53 in breast carcinomas in relation to mutation status and clinical parameters

Lars O Baumbusch¹ , Simen Myhre¹ , Anita Langerød¹ , Anna Bergamaschi¹^,4 , Stephanie B Geisler² , Per E Lønning² , Wolfgang Deppert³ , Irene Dornreiter³ and Anne-Lise Børresen-Dale¹^,4

¹Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, 0310 Oslo, Norway

²Department of Medicine, Section of Oncology, Haukeland University Hospital, 5021 Bergen, Norway

³Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistr. 52, 20251 Hamburg, Germany

⁴Medical Faculty, University of Oslo, Oslo, Norway

author email corresponding author email

Molecular Cancer 2006, 5:47doi:10.1186/1476-4598-5-47


Published:	20 October 2006

Abstract

Background

The tumor suppressor gene p53 (TP53) controls numerous signaling pathways and is frequently mutated in human cancers. Novel p53 isoforms suggest alternative splicing as a regulatory feature of p53 activity.

Results

In this study we have analyzed mRNA expression of both wild-type and mutated p53 and its respective Δp53 isoform in 88 tumor samples from breast cancer in relation to clinical parameters and molecular subgroups. Three-dimensional structure differences for the novel internally deleted p53 isoform Δp53 have been predicted. We confirmed the expression of Δp53 mRNA in tumors using quantitative real-time PCR technique. The mRNA expression levels of the two isoforms were strongly correlated in both wild-type and p53-mutated tumors, with the level of the Δp53 isoform being approximately 1/3 of that of the full-length p53 mRNA. Patients expressing mutated full-length p53 and non-mutated (wild-type) Δp53, "mutational hybrids", showed a slightly higher frequency of patients with distant metastasis at time of diagnosis compared to other patients with p53 mutations, but otherwise did not differ significantly in any other clinical parameter. Interestingly, the p53 wild-type tumors showed a wide range of mRNA expression of both p53 isoforms. Tumors with mRNA expression levels in the upper or lower quartile were significantly associated with grade and molecular subtypes. In tumors with missense or in frame mutations the mRNA expression levels of both isoforms were significantly elevated, and in tumors with nonsense, frame shift or splice mutations the mRNA levels were significantly reduced compared to those expressing wild-type p53.

Conclusion

Expression of p53 is accompanied by the functionally different isoform Δp53 at the mRNA level in cell lines and human breast tumors. Investigations of "mutational hybrid" patients highlighted that wild-type Δp53 does not compensates for mutated p53, but rather may be associated with a worse prognosis. In tumors, both isoforms show strong correlations in different mutation-dependent mRNA expression patterns.