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Human Molecular Genetics Advance Access originally published online on January 25, 2006
Human Molecular Genetics 2006 15(5):777-787; doi:10.1093/hmg/ddi492
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Differential expression of novel naturally occurring splice variants of PTEN and their functional consequences in Cowden syndrome and sporadic breast cancer

Shipra Agrawal1,3,4 and Charis Eng1,2,5,*

1Genomic Medicine Institute, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Mailcode NE-50, Cleveland, OH 44195, USA, 2Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA, 3Human Cancer Genetics Program, Comprehensive Cancer Center and 4Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA and 5Cancer Research, UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK

* To whom correspondence should be addressed. Tel: +1 2164443440; Fax: +1 2166360655; Email: engc{at}ccf.org or spsmce{at}netscape.net

Received December 14, 2005; Accepted January 18, 2006

PTEN, a dual-phosphatase tumor suppressor, is inactivated in Cowden syndrome (CS), characterized by high risk of breast and thyroid cancer, and in variety of sporadic cancers. Despite the importance of alternative splicing, very limited information on its role in PTEN and associated cancers is available. We identified eight novel PTEN splice variants (SVs) that retained intron 3 regions (3a, 3b, 3c); intron 5 regions (5a, 5b, 5c); excluded part of exon 5 (DelE5) or all of exon 6 (DelE6), respectively. Analysis of SVs in 12 sporadic breast cancers revealed full-length (FL)-PTEN transcript reduction in 10; SVs 3b, 3c and 5c not expressed in 7, 6 and 4, respectively, and under-expressed in the rest. In contrast, SV-5b was over-expressed in breast cancers. PTEN SV analysis in 16 CS/CS-like patients and eight controls revealed that SV-5a is under-expressed and SV-3a over-expressed in the germline of CS/CS-like individuals when compared with controls. Although SV-5a expression decreased P-Akt level and cyclin D1 promoter activity, SVs 5b and 5c increased cyclin D1 promoter activity. Thus, SV-5a behaving like FL-PTEN corroborates our observation that SV-5a is under-expressed in CS when compared with controls. Similarly, SV-5b functionally counters PTEN's action and is over-expressed in sporadic breast cancers. Furthermore, we demonstrate that expression of these SVs is under the regulation of p53. Our observations suggest that differential expression of PTEN and its SVs could play a role in the pathogenesis of sporadic breast cancers and CS, and may lend a novel way of making a rapid molecular diagnosis of CS without mutation analysis.


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