The promoter and the enhancer region of the KLK 3 (prostate specific antigen) gene is frequently mutated in breast tumours and in breast carcinoma cell lines

KLK3 or prostate specific antigen (PSA) is a serine protease, which is an e stablished tumour marker of prostatic adenocarcinoma. PSA is now used widel y for the diagnosis and monitoring of patients with prostate cancer. Recent studies have demonstrated that about 70% of breast cancers produce PSA. In this study, we examined the molecular mechanism underlying the expression of the PSA gene in breast cancer and breast cancer cell lines. We analysed nine breast tumours categorized on the basis of high- or low-PSA expression in tumour cytosols and four breast cancer cell lines. To determine abnorma lities associated with PSA expression in breast tumours, genomic DNA was ex tracted and all five exons of the PSA gene were polymerase chain reaction ( PCR) amplified and sequenced on both strands. PCR amplification was also pe rformed for the promoter and enhancer elements of the PSA gene. No mutation s were observed in the coding portion of the gene. A polymorphism was obser ved in exon 2 from three breast tumours. However, sequencing of the promote r and the enhancer elements of the PSA gene reveals several point mutations . Within a 5.8-kb promoter/enhancer region of the PSA gene, we detected 16 different mutational hotspots (appearing more than once in the nine tumours ). Among these hotspots, two appeared in seven out of nine tumours. Most im portantly the androgen response element (ARE I) in the proximal promoter wa s found mutated in four tumours and in the breast carcinoma cell line MCF-7 . Mutations associated with the ARE I have been shown previously to result in an 80% decrease in PSA gene expression. The mutations in the core enhanc er and promoter region probably contribute to the aberrant expression of th e PSA gene in breast tumours, possibly by altering the regulation of the ge ne by steroid hormones.