Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Prostate cancer specific mutations of p53 differ in their ability to promote prostate cancer

SD Downing MSc, P Tam BSc, D Voeks PhD, R Martiniello-Wilks PhD, M Daja PhD, P Jackson PhD, PJ Russell PhD

Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW; Faculty of Medicine, University of New South Wales, Sydney, NSW; Australia,

P53 mutations occur mainly in late stage prostate cancer (PC) in association with androgen-independence, metastases and poor prognosis, but also occur in ~30% of early cancers. Unlike other cancers, in PC, p53 mutations rarely affect functionally inactivating hotspot residues, and their significance is unknown. AIM: We investigated the functional characteristics of p53 mutations reported in clinical specimens of PC to determine whether they lead to more aggressive disease. METHODS: Plasmid vectors expressing mutant p53 proteins were constructed and used to investigate the ability of mutant proteins to directly regulate expression of p53 target genes and to transform primary rodent cells. Stable LNCaP transfectants were used to examine the effects of mutant p53 proteins on expression of genes important in metastasis and implanted into the prostate of nude mice to determine metastatic potential. RESULTS: Mutations within p53 exons 5-8 were mostly transcriptionally defective and dominant-negative over wild type (wt) activity. Exon 4 or 10 mutations showed variable activity depending on the promoter or presence of wt p53. Half could transform primary rodent cells. The stable transfectants expressed increased levels of PSA and MMP-1 but less KAI1. Tumours formed by these cells were larger than those from cells with wt only p53 and one line caused gross metastases. CONCLUSIONS: Our data suggest that p53 mutations reported in PC show varying degrees of functional defects but are all associated with changes in gene expression designed to promote the progression of disease and metastasis.

KEY WORDS: mutant p53, transcription, stable transfectants, LNCaP, orthotopic implantation, prostate cancer.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on genetic risk assessment.