Expression of wild-type and mutated TP53in breast carcinomas
© BioMed Central 2005
Published: 17 June 2005
The tumor suppressor gene TP53 encodes a transcription factor controlling numerous cellular growth and signaling pathways, and thus it has been entitled the safeguard of genome integrity. The TP53 activity is regulated through several mechanisms including transcription and translation control, protein stability and interaction, and subcellular localization. TP53 reacts to a variety of cellular stress responses. The gene is frequently mutated in human cancers, and cells with inactivated TP53 protein are able to resist cell cycle arrest, DNA repair or apoptosis.
We assessed TP53 mRNA expression in 88 tumor samples from breast cancer patients with locally advanced disease using the real-time quantitative RT-PCR technique. Real-time PCR was carried out on the ABI Prism 7000 sequence detection system (TaqMan; Applied Biosystems, Foster City, CA, USA). All relative quantity values of TP53 mRNA were normalized to the average mRNA levels of two independent endogenous control references.
Results and conclusions
The TP53 mRNA intensities in human breast tumors exhibit a specific mutational pattern. In tumors with missense or in-frame mutations mRNA expression levels are significantly elevated compared with wild-type TP53, and in tumors with non-sense, frame-shift or splice mutations mRNA expression levels are significantly reduced compared with the wild-type TP53 mRNA expression. Consequently, distinctive groups based on the mRNA expression levels and mutation type can be created as wild type, group I (missense and in-frame mutations) or group II (nonsense, frame-shift and splice mutations). These three groups show significant differences in relation to patient progesterone receptor status, C-ERBB2/HER status, tumor grade, distribution of the different breast cancer subtypes and survival rates.
Interestingly, the TP53 wild type shows a wide range of mRNA expression. The lowest or highest quartiles of wild-type TP53 mRNA expression are significantly correlated to the patient estrogen receptor status, tumor grade and distribution of the different breast cancer subtypes.
Since TP53 interacts with various other tumor suppressor genes and oncogenes, mRNA transcript levels of HDM2, CDC37, C-MYC, and others have been determined, and their relation to the TP53 mRNA expression pattern are under further investigation.
The present study was supported by The National Programme for Research in Functional Genomics in Norway (FUGE), The Research Council of Norway.