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1 September 2008
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Cowden’s disease is an autosomal dominant disorder characterized by the development of multiple mucocutaneous lesions and benign tumors, and enhanced cancer predisposition. Germline somatic mutations in the PTEN tumor suppressor gene are observed in the majority of Cowden’s disease patients, which results in the reduced activity of the PTEN protein, a lipid phosphatase that restrains the PI3K-Akt-mTOR signaling pathway. The ability to translate this information into effective therapeutic strategies for Cowden’s disease, however, has been hampered by the limited availability of suitable animal models for this cancer-prone syndrome. As Cowden’s disease is characterized by the high incidence of epithelial-derived tumors, we selectively inactivated Pten in this cellular compartment in mice. These mice developed a number of tumoral lesions recapitulating most of the pathognomonic lesions characterizing Cowden’s disease, thereby providing an opportunity to explore the efficacy of interfering with the PI3K/Akt pathway as a therapeutic approach in this tumor-prone syndrome. Analysis of the status of phosphorylation of Akt (pAktThr308 and pAktSer473), S6 (p-S6), and proliferating nuclear antigen (PCNA) in the skin revealed that the Akt-mTOR pathway is highly active in epithelial lesions resulting from Pten inactivation. Inhibition of mTOR by rapamycin dramatically reduced p-S6 and pAktSer473, and decreased cell proliferation. Furthermore, the prolonged treatment with rapamycin promoted the rapid regression of advanced Cowden’s disease–like lesions, and prevented their development if the treatment is initiated soon after birth, before disease manifestation. These findings suggest that the blockade of mTOR with rapamycin and its analogs may represent a suitable therapeutic option for chemoprevention and treatment of Cowden’s disease patients and others tumor syndromes that involve defective PTEN function. For details, see the article by Squarize et al. on page 7066 of this issue.Close Modal - PDF Icon PDF LinkTable of Contents
ISSN 0008-5472
EISSN 1538-7445
Issue Sections
Journal Archive
Cancer Research (1941-Present; volumes 1-current)
(ISSN 0008-5472) Published twice monthly since 1987. From 1941-1986, published monthly.The American Journal of Cancer (1931-1940; volumes 15-40)
(ISSN 0099-7374) Published quarterly in 1931, bimonthly in 1932, and monthly from 1933 to 1940. The journal changed title to Cancer Research in 1941.The Journal of Cancer Research (1916-1930); volumes 1-14)
(ISSN 0099-7013) Published quarterly from 1916 through 1930 (publication was suspended from November 1922 to March 1924). The journal changed title to The American Journal of Cancer in 1931.Table of Contents
AACR Centennial Series
Review
Priority Reports
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Clinical Research
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Endocrinology
Epidemiology
Experimental Therapeutics, Molecular Targets, and Chemical Biology
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Tumor Microenvironment
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Corrections
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