PTEN: An Introduction

PTEN is a tumor suppressor: The PTEN tumor suppressor gene is a dual specificity phosphatase located on chromosome 10 (10q23) that acts through an Akt-dependent pathway to suppress cell division ands enable apoptosis (1-3) .  Its  role in tumor suppression is confirmed by frequent endometrial abnormalities which develop in PTEN-deficient mice (4-6)  and high incidence of breast, thyroid, and endometrial cancers in humans with constitutive mutation of one PTEN allele, Cowden’s syndrome (7-9).   

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Proliferative (53146 bytes) 17 Day Secretory (53549 bytes) 24 Day Secretory (48634 bytes) Menstrual (40112 bytes)

Nomal Endometrial Expression (above figs.) is hormone dependent: Endometrial gland PTEN expression changes with the hormonal environment during the normal menstrual cycle(10) .  Estrogenic conditions (proliferative) produce very high epithelial expression (left panel above).  Progesterone exposure during the secretory phase initially creates PTEN-free secretory vacuoles, then progressive depletion of PTEN protein (middle 2 panels, above).    PTEN protein eventually disappears from glands, and remains so during menses (right, above).  Stromal expression remains high throughout the cycle, but with variation in relative intensity between nuclear and cytoplasmic compartments. If  presence of a gene product corresponds to a functional requirement, it might be inferred that under progestin rich conditions of secretory endometrium the tumor suppressive activities of the PTEN protein are unnecessary.   This could explain why sporadically occurring PTEN mutations are more likely to progress to carcinoma in women on unopposed estrogens.

Mutant PTEN clones originate in "Normal" Endometrium: 43% of histologically normal proliferative endometrium contain rare glands that have lost the ability to express PTEN protein due to mutation or deletion of the PTEN gene itself (14).  These PTEN mutant clones persist between menstrual cycles, providing a reservoir of "first hit" cells over a protracted interval.  Since only 2.5% of women will ever get endometrial cancer, progression efficiency of these early stages to carcinoma is highly inefficient.  This is the reason that modulaters of progression efficiency (such as hormonal environment, and conditions that change the basal mutation rate) are such strong co-determinants of cancer risk.

Mutation in Endometrial Neoplasia: Mutations and deletions of the PTEN tumor suppressor gene are the most common genetic change yet found in endometrial adenocarcinoma, with estimates of the mutational rate ranging from 34-83% (11;12) .  The highest mutational rates are seen in endometrioid types of endometrial adenocarcinomas which are preceded by a premalignant lesion (11) .  PTEN mutations are acquired during the premalignant phases of tumorigenesis (11;13-16) .   Using a subset of tissues from the Endometrial Precancer Type Collection (17;18) , 55% of  computerized morphometry-defined precancerous (EIN, D-Score<0) lesions were seen to have PTEN mutations.

 Reference List

(1)     Kanamori Y, Kigawa J, Itamochi H, Shimada M, Takahashi M, Kamazawa S et al. Correlation between Loss of PTEN Expression and Akt Phosphorylation in Endometrial Carcinoma. Clin Cancer Res 2001; 7(4):892-895.

(2)     Kurose K, Zhou X, Araki T, Cannistra S, Maher E, Eng C. 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 2001; In Press.

(3)     Mutter GL. PTEN, a protean tumor suppressor. Am J Pathol 2001; 158:1895-1898. .

(4)     Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998; 19:348-355.

(5)    Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 1999; 96:1563-8.

(6)     Stambolic V, Tsao MS, Macpherson D, Suzuki A, Chapman WB, Mak TW. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res 2000; 60(13):3605-3611.

(7)     Eng C. Cowden syndrome. J Genet Counsel 1997; 6:181-191.

(8)     Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet 1997; 16:64-67.

(9)     Marsh D, Coulon V, Lunetta K, Rocca-Serra P, Dahia P, Zheng Z et al. Mutation spectrum and genotype-phenotype analyses in Cowden Disease and Bannayan-Zonana Syndrome, 2 hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 1998; 7:507-515.

(10)   Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Ziebold U, Eng C. Changes in endometrial PTEN expression throughout the human menstrual cycle. J Clin Endocrinol Metab 2000; 85:2334-2338.

(11)   Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JPA, Lees J et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924-930.

(12)   Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997; 57:3935-3940.

(13)   Levine RL, Cargile CB, Blazes MS, Van Rees B, Kurman RJ, Ellenson LH. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res 1998; 58:3254-3258.

(14)   Mutter GL, Ince TA, Baak JPA, Kust G, Zhou X, Eng C. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res,6:4311-4314, 2001..

(15)   Maxwell G, Risinger J, Gumbs C, Shaw H, Bentley R, Barrett J et al. Mutation of the PTEN tumor supressor gene in endometrial hyperplasias. Cancer Res 1998; 58:2500-2503.

(16)    Yoshinaga K, Sasano H, Furukawa T, Yamakawa H, Yuki M, Sato S et al. The PTEN, BAX, and IGFIIR genes are mutated in endometrial atypical hyperplasia. Jpn J Cancer Res 1998; 89(10):985-990.

(17)   Mutter GL, Baak JPA, Crum CP, Richart RM, Ferenczy A, Faquin WC. Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry. J Pathol 2000; 190:462-469.

(18)   Mutter GL. Endometrial Precancer Type Collection [On Line]. Available: http://www.endometrium.org 2001.

 

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