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• W2015323062 abstract "The molecular biology of the PTEN tumor suppressor gene is as multifaceted as the range of sporadic human malignancies in which it has been implicated. Multiple mechanisms can inactivate PTEN in glioblastoma, melanoma, and carcinomas of the thyroid, breast, prostate, endometrium, and ovary. Initial impressions, based on mutational analysis alone, that ovarian cancer PTEN inactivation is infrequent bear revision in light of a 27% frequency of lost PTEN protein expression reported by Kurose and colleagues in this issue of The American Journal of Pathology.1Kurose 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; 158: 2097-2106Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar Only 8% of PTEN protein nonexpressing ovarian adenocarcinomas are explained by combined allelic imbalance (loss of heterozygosity) and mutation, suggesting that transcriptional silencing by epigenetic mechanisms may be yet an additional means of modifying PTEN activity. Although they show for ovarian carcinoma that PTEN function can be delimited by an identifiable and consistent repertoire of downstream effectors, such as the Akt pathway, the consequences of PTEN inactivation are nonuniform in different tissues. Thus, in the endometrium PTEN acts as a gatekeeper for initiation of carcinogenesis, yet in prostate cancer and melanoma it defines a much later event, metastasis. Tissue context determines the molecular events that inactivate PTEN and heavily modify the resultant phenotype.A Multitude of Inactivating MechanismsFunctional inactivation of the PTEN gene may occur through deletional and mutational mechanisms, and these are variably invoked between tumor types (Table 1) and hereditary/sporadic settings. Thus, it is necessary to have an integrated and comprehensive snapshot of different modalities of PTEN inactivation before an accurate model of changing PTEN function can be concluded for a specific tumor type. Patients with Cowden syndrome have a high incidence of breast cancer caused by heritable constitutive structural mutations of the PTEN gene,2Liaw D Marsh DJ Li J Dahia PL Wang SI Zheng Z Bose S Call KM Tsou HC Peacocke M Eng C Parsons R Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.Nat Genet. 1997; 16: 64-67Crossref PubMed Scopus (1681) Google Scholar, 3Nelen MR van Staveren WC Peeters EA Hassel MB Gorlin RJ Hamm H Lindboe CF Fryns JP Sijmons RH Woods DG Mariman EC Padberg GW Kremer H Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.Hum Mol Genet. 1997; 6: 1383-1387Crossref PubMed Scopus (407) Google Scholar, 4Tsou HC Teng DH Ping XL Brancolini V Davis T Hu R Xie XX Gruener AC Schrager CA Christiano AM Eng C Steck P Ott J Tavtigian SV Peacocke M The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases.Am J Hum Genet. 1997; 61: 1036-1043Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar yet such mutations are rarely seen in sporadic breast cancer. Rather, the PTEN lesions of sporadic breast cancers are a deletion-induced hemizygous state.5Rhei E Kang L Bogomolniy F Federici MG Borgen PI Boyd J Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas.Cancer Res. 1997; 57: 3657-3659PubMed Google Scholar, 6Teng D Hu R Lin H Davis T Iliev D Frye C Swedlund B Hansen K Vinson V Gumpper K Ellis L El-Naggar A Frazier M Jassr S Langford L Lee J Mills G Pershouse M Pollack R Tornos C Troncoso P Yung W Fujii G Berson A Bookstein R Bolen J Tavtigian S Steck P MMAC1/PTEN Mutations in primary tumor specimens and tumor cell lines.Cancer Res. 1997; 57: 5221-5225PubMed Google Scholar, 7Perren A Weng L Boag A Ziebold U Thakore K Dahia P Lees J Mulligan L Mutter GL Eng C Immunocytochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast.Am J Pathol. 1999; 155: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar Deletion of the PTEN region at 10q23 are also predominant findings in PTEN-deficient melanomas8Celebi JT Shendrik I Silvers DN Peacocke M Identification of PTEN mutations in metastatic melanoma specimens.J Med Genet. 2000; 37: 653-657Crossref PubMed Scopus (83) Google Scholar, 9Zhou XP Gimm O Hampel H Niemann T Walker MJ Eng C Epigenetic PTEN silencing in malignant melanomas without PTEN mutation.Am J Pathol. 2000; 157: 1123-1128Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and glioblastomas.10Li J Yen C Liaw D Podsypanina K Bose S Wang SI Puc J Miliaresis C Rodgers L McCombie R Bigner SH Giovanella BC Ittmann M Tycko B Hibshoosh H Wigler MH Parsons R PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.Science. 1997; 275: 1943-1947Crossref PubMed Scopus (4234) Google Scholar, 11Rasheed BK Stenzel TT McLendon RE Parsons R Friedman AH Friedman HS Bigner DD Bigner SH PTEN gene mutations are seen in high-grade but not in low-grade gliomas.Cancer Res. 1997; 57: 4187-4190PubMed Google Scholar, 12Wang SI Puc J Li J Bruce JN Cairns P Sidransky D Parsons R Somatic mutations of PTEN in glioblastoma multiforme.Cancer Res. 1997; 57: 4183-4186PubMed Google Scholar, 13Bostrom J Cobbers JM Wolter M Tabatabai G Weber RG Lichter P Collins VP Reifenberger G Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q.Cancer Res. 1998; 58: 29-33PubMed Google Scholar, 14Fults D Pedone CA Thompson GE Uchiyama CM Gumpper KL Iliev D Vinson VL Tavtigian SV Perry WL Microsatellite deletion mapping on chromosome 10q and mutation analysis of MMAC1, FAS, and MXI1 in human glioblastoma multiforme.Int J Oncol. 1998; 12: 905-910PubMed Google Scholar, 15Tohma Y Gratas C Biernat W Peraud A Fukuda M Yonekawa Y Kleihues P Ohgaki H PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas.J Neuropathol Exp Neurol. 1998; 57: 684-689Crossref PubMed Scopus (215) Google Scholar In contrast, both PTEN deletion and mutation are frequent events in sporadic endometrioid endometrial adenocarcinoma.16Risinger JI Hayes AK Berchuck A Barrett JC PTEN/MMAC1 mutations in endometrial cancers.Cancer Res. 1997; 57: 4736-4738PubMed Google Scholar, 17Tashiro H Blazes MS Wu R Cho KR Bose S Wang SI Li J Parsons R Ellenson LH Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies.Cancer Res. 1997; 57: 3935-3940PubMed Google Scholar, 18Risinger JI Hayes K Maxwell GL Carney ME Dodge RK Barrett JC Berchuck A PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics.Clin Cancer Res. 1998; 4: 3005-3010PubMed Google Scholar, 19Simpkins SB Peiffer-Schneider S Mutch DG Gersell D Goodfellow PJ PTEN mutations in endometrial cancers with 10q LOH: additional evidence for the involvement of multiple tumor suppressors.Gynecol Oncol. 1998; 71: 391-395Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 20Bussaglia E del Rio E Matias-Guiu X Prat J PTEN mutations in endometrial carcinomas: a molecular and clinicopathologic analysis of 38 cases.Hum Pathol. 2000; 31: 312-317Abstract Full Text PDF PubMed Scopus (148) Google Scholar, 21Mutter GL Lin MC Fitzgerald JT Kum JB Baak JPA Lees J Weng LP Eng C Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.J Natl Cancer Inst. 2000; 92: 924-930Crossref PubMed Google Scholar It should be remembered that technical variation can confound reproducibility of loss of heterozygosity and mutational data between laboratories. Deletion and mutation detection is affected by the extent to which normal tissue contaminates isolated lesional DNA, a process that varies between investigators. For example, denaturing gradient gel electrophoresis (DGGE) is particularly suited for detecting as low as 1 to 10% mutant DNA contribution. These problems are not unique to PTEN, but are compounded when multiple mechanisms must be evaluated in a single tumor type. Many of the literature inconsistencies between reported involvement of the PTEN gene in specific tumor types can be attributed to the methodologies used. Ovarian carcinoma is an example where the impression of the extent of altered PTEN genotype has been highly dependent on whether mutation alone,22Maxwell GL Risinger JI Tong B Shaw H Barrett JC Berchuck A Futreal PA Mutation of the PTEN tumor suppressor gene is not a feature of ovarian cancers.Gynecol Oncol. 1998; 70: 13-16Abstract Full Text PDF PubMed Scopus (37) Google Scholar or deletion and mutation1Kurose 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; 158: 2097-2106Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 23Saito M Okamoto A Kohno T Takakura S Shinozaki H Isonishi S Yasuhara T Yoshimura T Ohtake Y Ochiai K Yokota J Tanaka T Allelic imbalance and mutations of the PTEN gene in ovarian cancer.Int J Cancer. 2000; 85: 160-165PubMed Google Scholar are evaluated.Table 1PTEN Lesions (Deletion and/or Mutation) in Sporadic Human MalignanciesPTEN inactivationSiteTumor typeRangeAverageCommentReference no.BrainGlioblastoma17–70%48% (107/224)Mostly LOH10–15BreastDuctal carcinoma15–48%37% (37/100)Mostly LOH6, 7EndometriumEndometrioid carcinoma34–83%42% (139/334)LOH and mutation16–21ProstateAdenocarcinoma17–41%33% (49/149)Mostly LOH43Rubin MA Gerstein A Reid K Bostwick DG Cheng L Parsons R Papadopoulos N 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2–3,N+) versus lymph node-negative (pT2–3,N0) prostate cancer.Hum Pathol. 2000; 31: 504-508Abstract Full Text PDF PubMed Scopus (51) Google Scholar, 45Gray IC Stewart LM Phillips SM Hamilton JA Gray NE Watson GJ Spurr NK Snary D Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN.Br J Cancer. 1998; 78: 1296-1300Crossref PubMed Scopus (130) Google Scholar, 46Dong JT Sipe TW Hyytinen ER Li CL Heise C McClintock DE Grant CD Chung LW Frierson HF PTEN/MMAC1 is infrequently mutated in pT2 and pT3 carcinomas of the prostate.Oncogene. 1998; 17: 1979-1982Crossref PubMed Scopus (85) Google ScholarOvaryCystadenocarcinoma6–45%33% (65/198)LOH and mutation1Kurose 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; 158: 2097-2106Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 22Maxwell GL Risinger JI Tong B Shaw H Barrett JC Berchuck A Futreal PA Mutation of the PTEN tumor suppressor gene is not a feature of ovarian cancers.Gynecol Oncol. 1998; 70: 13-16Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 23Saito M Okamoto A Kohno T Takakura S Shinozaki H Isonishi S Yasuhara T Yoshimura T Ohtake Y Ochiai K Yokota J Tanaka T Allelic imbalance and mutations of the PTEN gene in ovarian cancer.Int J Cancer. 2000; 85: 160-165PubMed Google Scholar, 24Obata K Morland SJ Watson RH Hitchcock A Chenevix-Trench G Thomas EJ Campbell IG Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors.Cancer Res. 1998; 58: 2095-2097PubMed Google Scholar, 47Yokomizo A Tindall DJ Hartmann L Jenkins RB Smith DI Liu W Mutation analysis of the putative tumor suppressor PTEN/MMAC1 in human ovarian cancer.Int J Oncol. 1998; 13: 101-105PubMed Google ScholarSkinMelanoma32–33%33% (18/55)Mostly LOH8, 9ThyroidCarcinoma37%37% (19/51)Mostly LOH44LOH, loss of heterozygosity. Open table in a new tab The mechanism of PTEN inactivation seems to be conserved in a given histological subtype of adenocarcinoma irrespective of the primary site. For example, PTEN inactivation in endometrioid adenocarcinomas of the ovary1Kurose 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; 158: 2097-2106Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 24Obata K Morland SJ Watson RH Hitchcock A Chenevix-Trench G Thomas EJ Campbell IG Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors.Cancer Res. 1998; 58: 2095-2097PubMed Google Scholar and endometrium18Risinger JI Hayes K Maxwell GL Carney ME Dodge RK Barrett JC Berchuck A PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics.Clin Cancer Res. 1998; 4: 3005-3010PubMed Google Scholar, 21Mutter GL Lin MC Fitzgerald JT Kum JB Baak JPA Lees J Weng LP Eng C Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.J Natl Cancer Inst. 2000; 92: 924-930Crossref PubMed Google Scholar have similar patterns of deletion and mutation. In contrast, PTEN mutation is quite rare in carcinomas with papillary serous differentiation irrespective of whether they occur in the ovary or endometrium. We can thus identify the histological mix24Obata K Morland SJ Watson RH Hitchcock A Chenevix-Trench G Thomas EJ Campbell IG Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors.Cancer Res. 1998; 58: 2095-2097PubMed Google Scholar of tumors as another variable that must be considered in comparing results from series of cases derived from a common site.Loss of PTEN function in endometrial,21Mutter GL Lin MC Fitzgerald JT Kum JB Baak JPA Lees J Weng LP Eng C Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.J Natl Cancer Inst. 2000; 92: 924-930Crossref PubMed Google Scholar breast,7Perren A Weng L Boag A Ziebold U Thakore K Dahia P Lees J Mulligan L Mutter GL Eng C Immunocytochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast.Am J Pathol. 1999; 155: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar prostate,25Whang YE Wu X Suzuki H Reiter RE Tran C Vessella RL Said JW Isaacs WB Sawyers CL Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression.Proc Natl Acad Sci USA. 1998; 95: 5246-5250Crossref PubMed Scopus (561) Google Scholar ovarian,1Kurose 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; 158: 2097-2106Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar and melanocytic9Zhou XP Gimm O Hampel H Niemann T Walker MJ Eng C Epigenetic PTEN silencing in malignant melanomas without PTEN mutation.Am J Pathol. 2000; 157: 1123-1128Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar tumors is more frequent than can be adequately explained by structural genomic changes alone. Careful exclusion of deletional and mutational mechanisms in these cases has led to the prediction of epigenetic mechanisms as yet another means by which this tumor suppressor can be silenced. Proving an epigenetic mechanism of PTEN silencing is technically nontrivial because of the large size (>250 kb) of its upstream regulatory region, the existence of a highly conserved processed pseudogene26Dahia P Fitzgerald M Zhang X Marsh D Zheng Z Pietsch T von Deimling A Haluska F Haber D Eng C A highly conserved processed PTEN pseudogene is located on chromosome band 9p21.Oncogene. 1998; 16: 2403-2406Crossref PubMed Scopus (76) Google Scholar with homology maintained up to 1 kb upstream of the translational start site, and technical challenges in linking epigenetic events with expression level. Recent reports of PTEN promoter methylation27Salvesen HB MacDonald N Ryan A Jacobs IJ Lynch ED Akslen LA Das S PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma.Int J Cancer. 2001; 91: 22-26Crossref PubMed Scopus (264) Google Scholar in endometrial cancer, and reacquisition of PTEN expression on treatment of prostate cancer cells with the demethylating agent 5-azadeoxycytidine25Whang YE Wu X Suzuki H Reiter RE Tran C Vessella RL Said JW Isaacs WB Sawyers CL Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression.Proc Natl Acad Sci USA. 1998; 95: 5246-5250Crossref PubMed Scopus (561) Google Scholar are consistent with epigenetic mechanisms at work in these models.Implication in Diverse Regulatory PathwaysIn vitro cell line data has suggested that the tumor suppressor functions of PTEN, including G1 arrest and enabling of apoptosis, are mediated by a cascade that maintains the putative downstream factor Akt in a dephosphorylated state.28Weng LP Smith WM Dahia P Ziebold U Lees J Eng C PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death.Cancer Res. 1999; 59: 5808-5814PubMed Google Scholar, 29Li J Simpson L Takahashi M Miliaresis C Myers MP Tonks N Parsons R The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene.Cancer Res. 1998; 58: 5667-5672PubMed Google Scholar Thus, the prediction that PTEN protein and phospho-Akt have an inverse quantitative relationship. The article by Kurose and colleagues1Kurose 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; 158: 2097-2106Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar (page xx, this issue) uses a series of primary sporadic ovarian cancers to confirm this inverse relationship between PTEN protein and phospho-Akt. This is an important extrapolation from a cell culture model, which is necessarily limited in representing the range of genetic variation and heterogeneity present in sporadic human tumors. Because the majority of ovarian cancers with elevated phospho-Akt levels are accompanied by demonstrable changes in PTEN function, PTEN presents itself as a major determinant of Akt-mediated apoptosis and G1arrest in ovarian cancer. Mitotic arrest and cell death are, however, basic cellular functions controlled by a complex web of regulatory pathways that probably include elements outside the PTEN-Akt axis. The finding that p27 and cyclin D1 do not necessarily behave according to a simple linear model aligned with PTEN and Akt1Kurose 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; 158: 2097-2106Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar suggests that these downstream events are indirect or subject to modification.Additional functions of PTEN outside the Akt pathway have been proposed, and are still under active experimental consideration. These include control of cell adhesion and migration by dephosphorylation of focal adhesion kinases.30Tamura M Gu J Matsumoto K Aota S Parsons R Yamada KM Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.Science. 1998; 280: 1614-1617Crossref PubMed Scopus (1073) Google Scholar, 31Tamura M Gu J Takino T Yamada KM Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas.Cancer Res. 1999; 59: 442-449PubMed Google Scholar Although this might explain some of the altered functions expected in neoplastic transformation, the effect of PTEN on adhesion is probably a complex one that likely involves other intermediary molecules.32Liliental J Moon SY Lesche R Mamillapalli R Li D Zheng Y Sun H Wu H Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases.Curr Biol. 2000; 10: 401-404Abstract Full Text Full Text PDF PubMed Scopus (254) Google ScholarNongenetic ModifiersThere must be as yet unidentified factors that are capable of significantly modifying the phenotypic presentation of cells with altered PTEN function. The constellation of sporadic human tumors characterized by PTEN inactivation (Table 1) only partly overlaps with that of the heritable cancer syndrome caused by constitutive PTEN inactivation, Cowden syndrome. Cowden syndrome is often accompanied by thyroid (mainly follicular histology), breast, and endometrial cancers and benign hamartomatous lesions of the skin and brain.33Eng C Will the real Cowden syndrome please stand up: revised diagnostic criteria.J Med Genet. 2000; 37: 828-830Crossref PubMed Scopus (445) Google Scholar Surprisingly, they have not been reported to have heightened incidences of ovarian and prostate adenocarcinomas or glioblastoma, sporadic tumor types that often have PTEN inactivation. One possible explanation is that existing series of Cowden syndrome patients are too small to precisely measure even significant changes in incidences of these tumors beyond their already low sporadic occurrence rates. There is also divergence of tumor spectrum between murine pten- deficient mice and human neoplasia. pten knockout mice develop papillary thyroid, breast, prostate, and endometrial tumors, but not glioblastomas or ovarian carcinoma.34Podsypanina K Ellenson LH Nemes A Gu J Tamura M Yamada KM Cordon-Cardo C Catoretti G Fisher PE Parsons R Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems.Proc Natl Acad Sci USA. 1999; 96: 1563-1568Crossref PubMed Scopus (828) Google Scholar, 35Stambolic 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: 3605-3611PubMed Google Scholar One constitutively pten- deficient mouse model36Suzuki A de la Pompa JL Stambolic V Elia AJ Sasaki T del BB I Ho A Wakeham A Itie A Khoo W Fukumoto M Mak TW High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice.Curr Biol. 1998; 8: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar resulted in lymphoproliferative lesions that are not seen in human Cowden syndrome and have not been otherwise associated with prominent somatic PTEN mutation. It is reasonable to postulate that a germ-line PTEN mutation such as knock-out murine models or Cowden patients may result in permanent compensatory changes during early development that in turn results in a different spectrum of tumors compared to sporadic somatic mutations. Thus, although heritable PTEN-deficient mice and Cowden patients have been useful in defining the tumor suppressor activity of PTEN, caution must be used in extrapolation between species, and to a sporadic setting.Hormonal environment is one systemic factor that may modulate physiological demand for PTEN protein, thereby defining a shifting normal baseline against which the functional implications of PTEN loss must be measured. Normal PTEN expression increases in endometrial glands during the estrogenic follicular phase of the menstrual cycle,37Mutter 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: 2334-2338Crossref PubMed Scopus (131) Google Scholar and declines dramatically on introduction of the antiestrogenic hormone progesterone. It is unknown whether estrogen-associated increases in endometrial PTEN expression is part of a general mitogenic response, or whether there is a direct upstream link between the estrogen response pathway and the PTEN gene. Whatever the case, it seems that a rapidly dividing estrogen-stimulated endometrial gland has a greater PTEN requirement than a quiescent progesterone-exposed nonmitotic gland, and it is reasonable to conclude that these settings would respond differently to loss of PTEN function. Consistent with this notion is the fact that the primary epidemiological risk factor for PTEN-deficient endometrial carcinomas (endometrioid histological subtype) is protracted estrogen exposure.38Parazzini F La Vecchia C Bocciolone L Franceschi S The epidemiology of endometrial cancer.Gynecol Oncol. 1991; 41: 1-16Abstract Full Text PDF PubMed Scopus (379) Google Scholar The possibility of hormonal regulation of PTEN protein in other tissue types is largely unexplored. There is, however, enticing preliminary data that suggests that PTEN may inhibit cell growth through the MAP kinase-dependent insulin response pathway in an in vitro breast cancer model.39Weng LP Smith WM Brown JL Eng C 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. 2001; 10: 605-616Crossref PubMed Scopus (176) Google ScholarEarly and Late Effects: Tumor Initiation Versus MetastasisIt is remarkable that PTEN inactivation may affect quite different stages of tumor evolution, being highly consistent in multiple examples of tumors at one site. In the case of endometrioid endometrial adenocarcinoma, loss of PTEN expression is usually invoked quite early on, in the manner of a gene that performs a gatekeeper function.40Ali IU Gatekeeper for endometrium: the PTEN tumor suppressor gene.J Natl Cancer Inst. 2000; 92: 861-863Crossref PubMed Scopus (55) Google Scholar PTEN mutation, deletion, and loss of expression are seen in the premalignant phases of endometrial carcinogenesis, and appear at highest frequency (83%) in those adenocarcinomas that are preceded by a histologically evident premalignant hyperplasia (EIN, endometrial intraepithelial neoplasia)21Mutter GL Lin MC Fitzgerald JT Kum JB Baak JPA Lees J Weng LP Eng C Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.J Natl Cancer Inst. 2000; 92: 924-930Crossref PubMed Google Scholar and have an indolent, nonaggressive clinical course. Loss of PTEN function may even precede acquisition of cytological atypia, a histopathological feature long thought to distinguish the threshold between benign and premalignant endometrial disease.21Mutter GL Lin MC Fitzgerald JT Kum JB Baak JPA Lees J Weng LP Eng C Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.J Natl Cancer Inst. 2000; 92: 924-930Crossref PubMed Google Scholar Clear cell and endometrioid ovarian adenocarcinomas may also share deletion of the PTEN locus41Obata K Hoshiai H Common genetic changes between endometriosis and ovarian cancer.Gynecol Obstet Invest. 2000; 50: 39-43Crossref PubMed Scopus (90) Google Scholar, 42Sato N Tsunoda H Nishida M Morishita Y Takimoto Y Kubo T Noguchi M 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. 2000; 60: 7052-7056PubMed Google Scholar with premalignant (endometriosis) tissues.42Sato N Tsunoda H Nishida M Morishita Y Takimoto Y Kubo T Noguchi M 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. 2000; 60: 7052-7056PubMed Google ScholarIn contrast, PTEN inactivation in melanoma,8Celebi JT Shendrik I Silvers DN Peacocke M Identification of PTEN mutations in metastatic melanoma specimens.J Med Genet. 2000; 37: 653-657Crossref PubMed Scopus (83) Google Scholar prostate carcinoma,43Rubin MA Gerstein A Reid K Bostwick DG Cheng L Parsons R Papadopoulos N 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2–3,N+) versus lymph node-negative (pT2–3,N0) prostate cancer.Hum Pathol. 2000; 31: 504-508Abstract Full Text PDF PubMed Scopus (51) Google Scholar and glioblastoma,11Rasheed BK Stenzel TT McLendon RE Parsons R Friedman AH Friedman HS Bigner DD Bigner SH PTEN gene mutations are seen in high-grade but not in low-grade gliomas.Cancer Res. 1997; 57: 4187-4190PubMed Google Scholar, 13Bostrom J Cobbers JM Wolter M Tabatabai G Weber RG Lichter P Collins VP Reifenberger G Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q.Cancer Res. 1998; 58: 29-33PubMed Google Scholar is a marker for an aggressive subset of tumors likely to metastasize. Although metastasis is considered to be a late event in tumor progression, PTEN inactivation in these cases probably occurs earlier in tumor evolution. Even for those prostatic carcinomas that have metastasized, PTEN deletions are already widely present at the primary site.43Rubin MA Gerstein A Reid K Bostwick DG Cheng L Parsons R Papadopoulos N 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2–3,N+) versus lymph node-negative (pT2–3,N0) prostate cancer.Hum Pathol. 2000; 31: 504-508Abstract Full Text PDF PubMed Scopus (51) Google Scholar Aggressive glioblastomas with PTEN loss of function are primarily high grade throughout, and PTEN inactivation does not often occur in" @default.
• W2015323062 created "2016-06-24" @default.
• W2015323062 creator A5021618100 @default.
• W2015323062 date "2001-06-01" @default.
• W2015323062 modified "2023-10-12" @default.
• W2015323062 title "PTEN, a Protean Tumor Suppressor" @default.
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