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Human Molecular Genetics Advance Access published online on January 25, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi492
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 14, 2005
Revised January 18, 2006
Accepted January 18, 2006

Article

Differential Expression of Novel Naturally Occurring Splice Variants of PTEN and their Functional Consequences in Cowden syndrome and Sporadic Breast Cancer

Shipra Agrawal 1 and Charis Eng 2 *

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

* To whom correspondence should be addressed.
Charis Eng, E-mail: engc{at}ccf.org or spsmce@netscape.net


  Abstract

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 8 novel PTEN splice variants (SVs), which 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 is reduced in 10, SVs 3b, 3c and 5c not expressed in 7, 6 and 4, respectively, and under-expressed in the remainder. In contrast, SV-5b was over-expressed in the breast cancers. PTEN SV analysis in 16 CS/CS-like patients and 8 controls revealed that SV-5a is under-expressed and SV-3a over-expressed in the germline of CS/CS-like individuals compared to controls. While SV-5a expression decreased P-Akt level and cyclinD1 promoter activity, SVs 5b and 5c increased cyclinD1 promoter activity. Thus, SV-5a behaving like FL-PTEN corroborates our observation that SV-5a is under-expressed in CS compared to 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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