Genetic Alterations of the p14ARF-hdm2-p53 Regulatory Pathway in Breast Carcinoma
| Autor: | Gay Hui Ho, Jacqueline E. Calvano, Maria Bisogna, Ziad Abouezzi, Patrick I. Borgen, Carlos Cordón-Cardó, Kimberly J. Van Zee |
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| Rok vydání: | 2001 |
| Předmět: |
Cancer Research
Tumor suppressor gene DNA Mutational Analysis Breast Neoplasms Biology medicine.disease_cause Exon Breast cancer p14arf Proto-Oncogene Proteins Tumor Suppressor Protein p14ARF Gene duplication Tumor Cells Cultured medicine Humans Gene silencing RNA Messenger Reverse Transcriptase Polymerase Chain Reaction Carcinoma Cell Cycle Gene Amplification Nuclear Proteins Proteins Proto-Oncogene Proteins c-mdm2 Exons Genes p53 medicine.disease Molecular biology Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Oncology Cancer research Female Breast carcinoma Carcinogenesis |
| Zdroj: | Breast Cancer Research and Treatment. 65:225-232 |
| ISSN: | 1573-7217 0167-6806 |
| DOI: | 10.1023/a:1010686518990 |
| Popis: | TP53 is the most commonly mutated tumor suppressor gene in human cancers. The amplification and overexpression of HDM2 plays a role in tumorigenesis via inactivation of p53-dependent cell cycle arrest. p14ARF, an alternate transcript of the INK4A tumor suppressor locus, prevents hdm2-induced transcriptional silencing of p53 by binding hdm2. The role of this p14ARF-hdm2-p53 regulatory pathway in breast carcinoma is unknown. We hypothesized that p14ARF mutations and HDM2 gene amplification may be alternative mechanisms of p53 inactivation in breast cancer. Mutational analysis of TP53 (exons 5-9) and exon 1beta of pl4ARF was performed by PCR-SSCP and putative mutations were confirmed by sequencing. p14ARF mRNA expression was evaluated by RT-PCR and the presence of HDM2 gene amplification by differential PCR. Among the cell lines, 7/14 (50%) harbored TP53 mutations and 2/14 (14%) had a deletion ofp14ARF exon 1beta with no detectable p14ARF mRNA. None demonstrated HDM2 gene amplification. TP53 mutations were identified in 7/36 (19%) breast tumors and HDM2 amplification in 2/30 (7%) tumors. All the tumors contained an intact p14ARF exon 1beta with corresponding expression of the mRNA. Alterations in the various components of this regulatory pathway were identified in nine (64%) cell lines and 25% of the 36 breast cancers with TP53 mutation being the predominant aberration. Although p14ARF mutations and HDM2 gene amplification appear to be uncommon events in breast carcinoma, deregulation of this pathway may occur via alternative mechanisms in breast carcinogenesis. |
| Databáze: | OpenAIRE |
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