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Breast carcinoma represents the most common malignancy of women in Western countries. Despite its prevalence, the molecular mechanisms of breast cancer formation and progression are still poorly understood. Molecular studies suggest that tumoursuppressor genes involved in hereditary tumour formation may also be altered in their sporadic counterparts (Fearon, 1997). Five per cent of all patients with breast carcinomas report a family history and the majority of these familial cases have been associated with germline mutations of the BRCA1 or BRCA2 tumoursuppressor genes (Miki et al, 1994;Wooster et al, 1995). However, the BRCA1 and BRCA2 genes are not usually altered in sporadic breast carcinomas (Lancaster et al, 1996;Miki et al, 1996), although loss of heterozygosity (LOH) in the BRCA1 and BRCA2 on chromosomal arms 17q and 13q is frequently observed (Schmutzler et al, 1997).Recently, the PTEN/MMAC1/TEP1 tumour-suppressor gene has been identified on chromosomal band 10q23.3 (Li and Sun, 1997;. The product of this gene harbours a tyrosine phosphatase domain which shares high sequence homology with the cytoskeleton proteins tensin and auxilin. Mutations of PTEN were observed in a variety of tumours including breast carcinoma cell lines and primary invasive breast carcinomas . These mutations included homozygous deletions and frameshift or nonsense mutations. Moreover, loss of heterozygosity affecting 10q23.3 was detected in as many as 50% of primary breast carcinomas. Germline mutations of PTEN have been identified in Cowden disease, a rare autosomal dominant cancer syndrome characterized by malignancies of the breast, thyroid and brain . These observations point to PTEN as an interesting candidate for a tumour-suppressor gene associated with breast cancer.Recent studies on sporadic tumours demonstrated that mutations in the PTEN gene are frequent events in glioblastomas, malignant melanomas and endometrial carcinomas of the endometrioid type (Guldberg et al, 1997;Kong et al, 1997;Rasheed et al, 1997;Tashiro et al, 1997;Wang et al, 1997). In endometrial carcinomas, PTEN mutations were predominantly found in tumours with microsatellite instability (Kong et al, 1997;Tashiro et al, 1997). It remains to be shown whether the association of PTEN mutations and microsatellite instability is of biological significance. In a series of 54 sporadic breast carcinomas, two deletions resulting in truncated proteins and various missense mutations of unknown significance have been reported (Rhei et al, 1997). To further elucidate the potential role of PTEN in breast carcinomas, we analysed 103 sporadic breast carcinomas for mutations, homozygous deletions and loss of heterozygosity, and 25 families with hereditary breast cancer for constitutive mutations in the PTEN gene. MATERIALS AND METHODS Tumour specimens from sporadic breast carcinomas and blood samples from patients with hereditary breast carcinomasBreast cancer families were recruited at the University Hospital Bonn and the Department of Medical Genetics, University of Mun...

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Cytoplasmic polyadenylation element binding proteins (CPEBs) are auxiliary translational factors that associate with consensus sequences present in 3′UTRs of mRNAs, thereby activating or repressing their translation. Knowing that CPEBs are players in cell cycle regulation and cellular senescence prompted us to investigate their contribution to the molecular pathology of gliomas–most frequent of intracranial tumors found in humans. To this end, we performed methylation analyses in the promoter regions of CPEB1-4 and identified the CPEB1 gene to be hypermethylated in tumor samples. Decreased expression of CPEB1 protein in gliomas correlated with the rising grade of tumor malignancy. Abundant expression of CPEBs2-4 was observed in several glioma specimens. Interestingly, expression of CPEB3 positively correlated with tumor progression and malignancy but negatively correlated with protein phosphorylation in the alternatively spliced region. Our data suggest that loss of CPEB3 activity in high-grade gliomas is caused by expression of alternatively spliced variants lacking the B-region that overlaps with the kinase recognition site. We conclude that deregulation of CPEB proteins may be a frequent phenomenon in gliomas and occurs on the level of transcription involving epigenetic mechanism as well as on the level of mRNA splicing, which generates isoforms with compromised biological properties.

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