Exclusion of a major role for the PTEN tumour-suppressor gene in breast carcinomas

Abstract

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...

Common Genetic Variation at PTEN and Risk of Sporadic Breast and Prostate Cancer

“…utah.edu/genesnps; refs. 9,19). No associations with breast or prostate cancer risk have been reported; however, these studies have not been comprehensive with respect to surveying common genetic variation.…”

Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen

“…[29][30][31][32][33] There is an increased predilection for breast cancer caused by germline mutations of PTEN (lifetime risk 450% in patients with Cowden's disease) however, mutations are rare in sporadic breast cancer. [34][35][36] Previous studies have demonstrated association between loss of PTEN expression or reduced PTEN expression in breast cancer with stage, lymph node status, disease-related death, and loss of ER. [20][21][22][23][24]37 Two of these studies included small number of unselected cases.…”

Incidence of multiple primary cancers in a cohort of women diagnosed with breast cancer in southeast England

“…Genetic syndromes associated with a predisposition to thyroid cancer include Cowden disease (Liaw et al, 1997); ataxia telangiectasia (Swift et al, 1987); inherited multiple endocrine neoplasia type II (Schimke, 1984); familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) (Houlston and Stratton, 1995). However, few of these are considered to be an important cause of breast cancer (Warren et al, 1992;Fitzgerald et al, 1997;Freihoff et al, 1999;Inskip et al, 1999).…”