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From the Clinical Cancer Genetics and Human Cancer Genetics
Programs,*
Ohio State University Comprehensive Cancer
Center, Columbus, Ohio; the Dana-Farber Cancer Institute
and Harvard Medical School,
Boston,
Massachusetts; the Department of Pathology,
University of Zürich, Zürich, Switzerland; the Departments
of Pathology§
and
Paediatrics,¶
Queen's University, Kingston,
Ontario, Canada; the Department of Biology,||
Cancer
Research Center, Massachusetts Institute of Technology, Cambridge,
Massachusetts; the Department of Pathology,**
Brigham and Women's Hospital and Harvard Medical School, Boston,
Massachusetts; and the CRC Human Cancer Genetics Research
Group,
University of Cambridge,
Cambridge, United Kingdom
Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3, cause Cowden syndrome (CS), which is characterized by a high risk of breast and thyroid cancers. Loss of heterozygosity of 10q22–24 markers and somatic PTEN mutations have been found to a greater or lesser extent in a variety of sporadic component and noncomponent cancers of CS. Among several series of sporadic breast carcinomas, the frequency of loss of flanking markers around PTEN is approximately 30 to 40%, and the somatic intragenic PTEN mutation frequency is <5%. In this study, we analyzed PTEN expression in 33 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammary tissue had a distinctive pattern of expression: myoepithelial cells uniformly showed strong PTEN expression. The PTEN protein level in mammary epithelial cells was variable. Ductal hyperplasia with and without atypia exhibited higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples, 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN-positive tumors as well as in normal epithelium, the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immunostain negative group, all had hemizygous PTEN deletion but no structural alteration of the remaining allele. Thus, in these cases, an epigenetic phenomenon such as hypermethylation, -ecreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and 1 did not have any structural abnormality. Finally, clinicopathological features were analyzed against PTEN protein expression. Three of the 5 PTEN immunostain-negative carcinomas were also both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study.
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B. Dave, R. R. Eason, S.R. Till, Y. Geng, M. C. Velarde, T. M. Badger, and R. C.M. Simmen The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN Carcinogenesis, October 1, 2005; 26(10): 1793 - 1803. [Abstract] [Full Text] [PDF]
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J.-H. Chung and C. Eng Nuclear-Cytoplasmic Partitioning of Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Differentially Regulates the Cell Cycle and Apoptosis Cancer Res., September 15, 2005; 65(18): 8096 - 8100. [Abstract] [Full Text] [PDF]
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M. Mikhail, E. Velazquez, R. Shapiro, R. Berman, A. Pavlick, L. Sorhaindo, J. Spira, C. Mir, K. S. Panageas, D. Polsky, et al. PTEN Expression in Melanoma: Relationship with Patient Survival, Bcl-2 Expression, and Proliferation Clin. Cancer Res., July 15, 2005; 11(14): 5153 - 5157. [Abstract] [Full Text] [PDF]
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J.-H. Chung, M. E. Ginn-Pease, and C. Eng Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal-Like Sequences for Nuclear Import Mediated by Major Vault Protein Cancer Res., May 15, 2005; 65(10): 4108 - 4116. [Abstract] [Full Text] [PDF]
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L. H. Saal, K. Holm, M. Maurer, L. Memeo, T. Su, X. Wang, J. S. Yu, P.-O. Malmstrom, M. Mansukhani, J. Enoksson, et al. PIK3CA Mutations Correlate with Hormone Receptors, Node Metastasis, and ERBB2, and Are Mutually Exclusive with PTEN Loss in Human Breast Carcinoma Cancer Res., April 1, 2005; 65(7): 2554 - 2559. [Abstract] [Full Text] [PDF]
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I. Sansal and W. R. Sellers The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway J. Clin. Oncol., July 15, 2004; 22(14): 2954 - 2963. [Abstract] [Full Text] [PDF]
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A. Goel, C. N. Arnold, D. Niedzwiecki, J. M. Carethers, J. M. Dowell, L. Wasserman, C. Compton, R. J. Mayer, M. M. Bertagnolli, and C. R. Boland Frequent Inactivation of PTEN by Promoter Hypermethylation in Microsatellite Instability-High Sporadic Colorectal Cancers Cancer Res., May 1, 2004; 64(9): 3014 - 3021. [Abstract] [Full Text] [PDF]
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G. Choe, S. Horvath, T. F. Cloughesy, K. Crosby, D. Seligson, A. Palotie, L. Inge, B. L. Smith, C. L. Sawyers, and P. S. Mischel Analysis of the Phosphatidylinositol 3'-Kinase Signaling Pathway in Glioblastoma Patients in Vivo Cancer Res., June 1, 2003; 63(11): 2742 - 2746. [Abstract] [Full Text] [PDF]
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O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen Combined Loss of PTEN and p27 Expression Is Associated with Tumor Cell Proliferation by Ki-67 and Increased Risk of Recurrent Disease in Localized Prostate Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1474 - 1479. [Abstract] [Full Text] [PDF]
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H. Kurokawa and C. L. Arteaga ErbB (HER) Receptors Can Abrogate Antiestrogen Action in Human Breast Cancer by Multiple Signaling Mechanisms Clin. Cancer Res., January 1, 2003; 9(1): 511S - 515S. [Abstract] [Full Text] [PDF]
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 G. Li, G. W. Robinson, R. Lesche, H. Martinez-Diaz, Z. Jiang, N. Rozengurt, K.-U. Wagner, D.-C. Wu, T. F. Lane, X. Liu, et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland Development, September 1, 2002; 129(17): 4159 - 4170. [Abstract] [Full Text] [PDF]
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 X.-P. Zhou, A. Loukola, R. Salovaara, M. Nystrom-Lahti, P. Peltomaki, A. de la Chapelle, L. A. Aaltonen, and C. Eng PTEN Mutational Spectra, Expression Levels, and Subcellular Localization in Microsatellite Stable and Unstable Colorectal Cancers Am. J. Pathol., August 1, 2002; 161(2): 439 - 447. [Abstract] [Full Text] [PDF]
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L.-P. Weng, J. L. Brown, K. M. Baker, M. C. Ostrowski, and C. Eng PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway Hum. Mol. Genet., July 15, 2002; 11(15): 1687 - 1696. [Abstract] [Full Text] [PDF]
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F. M. Yakes, W. Chinratanalab, C. A. Ritter, W. King, S. Seelig, and C. L. Arteaga Herceptin-induced Inhibition of Phosphatidylinositol-3 Kinase and Akt Is Required for Antibody-mediated Effects on p27, Cyclin D1, and Antitumor Action Cancer Res., July 15, 2002; 62(14): 4132 - 4141. [Abstract] [Full Text] [PDF]
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 G L Mutter Diagnosis of premalignant endometrial disease J. Clin. Pathol., May 1, 2002; 55(5): 326 - 331. [Abstract] [Full Text] [PDF]
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 M M de Jong, I M Nolte, G J te Meerman, W T A van der Graaf, J C Oosterwijk, J H Kleibeuker, M Schaapveld, and E G E de Vries Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility J. Med. Genet., April 1, 2002; 39(4): 225 - 242. [Abstract] [Full Text] [PDF]
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M. A. Zysman, W. B. Chapman, and B. Bapat Considerations When Analyzing the Methylation Status of PTEN Tumor Suppressor Gene Am. J. Pathol., March 1, 2002; 160(3): 795 - 800. [Abstract] [Full Text] [PDF]
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X.-P. Zhou, S. Kuismanen, M. Nystrom-Lahti, P. Peltomaki, and C. Eng Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors Hum. Mol. Genet., February 1, 2002; 11(4): 445 - 450. [Abstract] [Full Text] [PDF]
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J. DiRenzo, S. Signoretti, N. Nakamura, R. Rivera-Gonzalez, W. Sellers, M. Loda, and M. Brown Growth Factor Requirements and Basal Phenotype of an Immortalized Mammary Epithelial Cell Line Cancer Res., January 1, 2002; 62(1): 89 - 98. [Abstract] [Full Text] [PDF]
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 J. I. Lee, J.-C. Soria, K. A. Hassan, A. K. El-Naggar, X. Tang, D. D. Liu, W. K. Hong, and L. Mao Loss of PTEN Expression as a Prognostic Marker for Tongue Cancer Arch Otolaryngol Head Neck Surg, December 1, 2001; 127(12): 1441 - 1445. [Abstract] [Full Text] [PDF]
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N. G. Robertson, B. L. Resendes, J. S. Lin, C. Lee, J. C. Aster, J. C. Adams, and C. C. Morton Inner ear localization of mRNA and protein products of COCH, mutated in the sensorineural deafness and vestibular disorder, DFNA9 Hum. Mol. Genet., October 1, 2001; 10(22): 2493 - 2500. [Abstract] [Full Text] [PDF]
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B. Kwabi-Addo, D. Giri, K. Schmidt, K. Podsypanina, R. Parsons, N. Greenberg, and M. Ittmann Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression PNAS, September 5, 2001; (2001) 201167798. [Abstract] [Full Text] [PDF]
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M. D. Ringel, N. Hayre, J. Saito, B. Saunier, F. Schuppert, H. Burch, V. Bernet, K. D. Burman, L. D. Kohn, and M. Saji Overexpression and Overactivation of Akt in Thyroid Carcinoma Cancer Res., August 1, 2001; 61(16): 6105 - 6111. [Abstract] [Full Text] [PDF]
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G. L. Mutter PTEN, a Protean Tumor Suppressor Am. J. Pathol., June 1, 2001; 158(6): 1895 - 1898. [Full Text] [PDF]
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K. Kurose, X.-P. Zhou, T. Araki, S. A. Cannistra, E. R. Maher, and C. Eng Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas Am. J. Pathol., June 1, 2001; 158(6): 2097 - 2106. [Abstract] [Full Text] [PDF]
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L.-P. Weng, J. L. Brown, and C. Eng PTEN coordinates G1 arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model Hum. Mol. Genet., March 1, 2001; 10(6): 599 - 604. [Abstract] [Full Text] [PDF]
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L.-P. Weng, W. M. Smith, J. L. Brown, and C. Eng PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model Hum. Mol. Genet., March 1, 2001; 10(6): 605 - 616. [Abstract] [Full Text] [PDF]
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L.-P. Weng, J. L. Brown, and C. Eng PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways Hum. Mol. Genet., February 1, 2001; 10(3): 237 - 242. [Abstract] [Full Text] [PDF]
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L.-P. Weng, O. Gimm, J. B. Kum, W. M. Smith, X.-P. Zhou, D. Wynford-Thomas, G. Leone, and C. Eng Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death Hum. Mol. Genet., February 1, 2001; 10(3): 251 - 258. [Abstract] [Full Text] [PDF]
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N. Sato, H. Tsunoda, M. Nishida, Y. Morishita, Y. Takimoto, T. Kubo, and M. Noguchi Loss of Heterozygosity on 10q23.3 and Mutation of the Tumor Suppressor Gene PTEN in Benign Endometrial Cyst of the Ovary: Possible Sequence Progression from Benign Endometrial Cyst to Endometrioid Carcinoma and Clear Cell Carcinoma of the Ovary Cancer Res., December 1, 2000; 60(24): 7052 - 7056. [Abstract] [Full Text]
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A. Perren, P. Komminoth, P. Saremaslani, C. Matter, S. Feurer, J. A. Lees, P. U. Heitz, and C. Eng Mutation and Expression Analyses Reveal Differential Subcellular Compartmentalization of PTEN in Endocrine Pancreatic Tumors Compared to Normal Islet Cells Am. J. Pathol., October 1, 2000; 157(4): 1097 - 1103. [Abstract] [Full Text] [PDF]
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X.-P. Zhou, O. Gimm, H. Hampel, T. Niemann, M. J. Walker, and C. Eng Epigenetic PTEN Silencing in Malignant Melanomas without PTEN Mutation Am. J. Pathol., October 1, 2000; 157(4): 1123 - 1128. [Abstract] [Full Text] [PDF]
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O. Gimm, T. Attie-Bitach, J. A. Lees, M. Vekemans, and C. Eng Expression of the PTEN tumour suppressor protein during human development Hum. Mol. Genet., July 1, 2000; 9(11): 1633 - 1639. [Abstract] [Full Text] [PDF]
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V. Stambolic, M.-S. Tsao, D. Macpherson, A. Suzuki, W. B. Chapman, and T. W. Mak High Incidence of Breast and Endometrial Neoplasia Resembling Human Cowden Syndrome in pten+/- Mice Cancer Res., July 1, 2000; 60(13): 3605 - 3611. [Abstract] [Full Text]
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 G. L. Mutter, M.-C. Lin, J. T. Fitzgerald, J. B. Kum, J. P. A. Baak, J. A. Lees, L.-P. Weng, and C. Eng Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers J Natl Cancer Inst, June 7, 2000; 92(11): 924 - 930. [Abstract] [Full Text] [PDF]
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 G. L. Mutter, M.-C. Lin, J. T. Fitzgerald, J. B. Kum, and C. Eng Changes in Endometrial PTEN Expression throughout the Human Menstrual Cycle J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2334 - 2338. [Abstract] [Full Text]
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O. Gimm, A. Perren, L.-P. Weng, D. J. Marsh, J. J. Yeh, U. Ziebold, E. Gil, R. Hinze, L. Delbridge, J. A. Lees, et al. Differential Nuclear and Cytoplasmic Expression of PTEN in Normal Thyroid Tissue, and Benign and Malignant Epithelial Thyroid Tumors Am. J. Pathol., May 1, 2000; 156(5): 1693 - 1700. [Abstract] [Full Text] [PDF]
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L.-P. Weng, W. M. Smith, P. L. M. Dahia, U. Ziebold, E. Gil, J. A. Lees, and C. Eng PTEN Suppresses Breast Cancer Cell Growth by Phosphatase Activity-dependent G1 Arrest followed by Cell Death Cancer Res., November 1, 1999; 59(22): 5808 - 5814. [Abstract] [Full Text] [PDF]
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 J. Torres and R. Pulido The Tumor Suppressor PTEN Is Phosphorylated by the Protein Kinase CK2 at Its C Terminus. IMPLICATIONS FOR PTEN STABILITY TO PROTEASOME-MEDIATED DEGRADATION J. Biol. Chem., January 5, 2001; 276(2): 993 - 998. [Abstract] [Full Text] [PDF]
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B. Kwabi-Addo, D. Giri, K. Schmidt, K. Podsypanina, R. Parsons, N. Greenberg, and M. Ittmann Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression PNAS, September 25, 2001; 98(20): 11563 - 11568. [Abstract] [Full Text] [PDF]
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