Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers

Mutter, George L.; Lin, Ming-Nan; Fitzgerald, Jeffrey T.; Kum, Jennifer B.; Baak, Jan P. A.; Lees, Jacqueline A.; Weng, Liang; Eng, Charis

doi:10.1093/jnci/92.11.924

Cited by 759 publications

(600 citation statements)

References 22 publications

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“…Type I, or endometrioid carcinomas, represents the majority of cases and may be found in premenopausal women exposed to excess levels of estrogen. The most common molecular alterations found in this subtype include PTEN inactivation [2], and mutations of K-ras [3], beta-catenin [4], or hMLH1/MSH2 [5]. These tumors frequently develop in a background of adenomatous hyperplasia.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

Jiang

Dowdy

Meng

et al. 2007

Gynecologic Oncology

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Objective-To characterize the molecular pathways involved in apoptosis following administration of histone deacetylase inhibitors to Type I and II endometrial cancer cells.Methods-Ark2, Ishikawa, and AN3 cell lines representing both Type I and II endometrial cancers were treated with various concentrations of oxamflatin and HDAC inhibitor-1. Cell apoptosis was determined by flow cytometry, nuclear staining, Western blotting, and mitochondrial membrane potential assays.Results-Compared to controls, there was a 95% reduction in the growth of Ark2 cells following administration of histone deacetylase inhibitors and this response was dose-dependent. These agents also caused profound morphologic changes and loss of mitochondrial membrane potentials consistent with the induction of apoptosis. Cleavage of PARP, caspase-9, and caspase-8 was detected, confirming the activation of apoptotic cascades in endometrial carcinoma cells. This effect was present in both serous and endometrioid cell types.Conclusion-Our results suggest that oxamflatin and HDAC inhibitor-1 have potent cytotoxicity in endometrial cancer cells by inducing cell apoptosis. Histone deacetylase inhibitors are promising agents for the treatment of both Type I and II endometrial carcinoma.

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Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

Jiang

Dowdy

Meng

et al. 2007

Gynecologic Oncology

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“…Although constitutive activation of Akt and/or PI3K is described in a growing list of solid tumors as a mechanism for transformation, [11][12][13][14][15] the most frequently mutated component of this pathway, by far, is PTEN, found to have an average mutation rate of 16% across many tumor types, to as high as 83% in endometrial cancers. 16 We have previously demonstrated that the PTEN protein is lost/reduced in 38% of human invasive breast cancers. 17 Our understanding of the signaling events that occur downstream of PTEN derives primarily from experimental models.…”

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confidence: 98%

The Akt pathway in human breast cancer: a tissue-array-based analysis

et al. 2006

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The Akt pathway, an important regulator of cell proliferation and survival, is deregulated in many cancers. The pathway has achieved considerable importance due to the development of kinase inhibitors that are able to successfully reduce tumor growth. This study was conducted to determine the status of the Akt pathway in human breast cancers and to study the relationship between the different component proteins. Expression levels of PTEN, phosphorylated forms of the constituent proteins (Akt, FKHR, mTOR, and S6) and cyclin D1 were evaluated by immunohistochemistry, on consecutive sections from a tissue microarray containing 145 invasive breast cancers and 140 pure ductal carcinomas in-situ. Aberrant expression was correlated statistically with tumor characteristics and disease outcome. The Akt pathway was found to be activated early in breast cancer, in the in-situ stage. In all, 33, 15, 32, and 60% of ductal carcinoma in-situ showed overexpression of Akt, FKHR, mTOR, and cyclin D1. PTEN loss did not correlate statistically with expression of AKT or any of the other proteins with the exception of S6, indicating that Akt activation was not a result of PTEN loss. Expression levels of PTEN and S6 were significantly different in in-situ and invasive cancers, indicating association with disease progression. Loss of PTEN was noted in 11% of in-situ as compared to 26% of invasive cancers, while S6 overexpression was seen in 47% in-situ and in 72% invasive cancers. High-grade carcinomas were associated with PTEN loss, while low-grade carcinomas with good prognostic features showed cyclin D1 overexpression and were associated with longer disease free survival. Additionally, cancers with mTOR overexpression showed a three times greater risk for disease recurrence. Overall, a large proportion of in-situ and invasive breast cancers overexpressed cyclinD1 and S6. Our results may have significant implications in the development and application of targeted therapy.

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“…Type I tumors exhibit endometrioid morphology, arise in the setting of increased estrogen exposure with subsequent development of precancerous lesions (endometrial intraepithelial hyperplasia-EIN/atypical hyperplasia), are associated with frequent PTEN inactivation mutations, and have a favorable outcome. 1,2 By contrast, Type II tumors demonstrate papillary serous or clear cell morphology, are not associated with any known precursor lesions, demonstrate frequent p53 mutations, and are associated with a poor outcome. 3,4 The differences between these groups are summarized in Table 1.…”

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confidence: 99%

Histologic and immunohistochemical decision-making in endometrial adenocarcinoma

et al. 2008

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Diffuse p53 immunostaining distinguishes 85% of serous (Type II) from endometrioid (Type I) carcinomas and is an independent marker for poor prognosis. Interobserver reproducibility for the diagnosis of these entities, as well as selection and prediction of p53 immunostaining results, is unknown. Reproducibility of three pathologists regarding: (1) a two (I and II) and (2) three part classification (I, II or indeterminate); (3) recommendation for p53 staining and (4) expectations of p53 staining results were computed with the kappa (k) statistic. All cases were immunostained for p53 and independently scored. A two and three tiered classification scheme achieved high (k ¼ 0.71) and moderate (k ¼ 0.49) reproducibility. Non-unanimous cases were more likely to be reclassified into an 'indeterminate' category (27 cases, 39% of passes) compared to those with unanimous (82 cases, 14% of passes) classification. Pathologists recommended p53 immunostaining with poor (k ¼ 0.28) reproducibility, but staining prediction was made with good concordance (69%, k ¼ 0.50). Moreover, p53 staining was more common in diagnostically discordant (46%) compared to concordant (16%) cases. A subset of endometrial cancers do not readily fit within a two-class system and can be culled from cases that (1) do not achieve interobserver concordance and (2) are more likely to be chosen for p53 immunostaining and (3) are more likely to stain positive for p53. Because p53 is an important marker for endometrial adenocarcinoma outcome, and cannot be predicted in advance in indeterminate cases, p53 immunostaining should be employed in cases with observer disagreement in a binary system. Keywords: p53; endometrial neoplasms; serous carcinoma; reproducibility Endometrial adenocarcinoma is a biologically diverse disease that has been divided into two subgroups based on histomorphology, biologic behavior, and underlying genetic aberrations. Type I tumors exhibit endometrioid morphology, arise in the setting of increased estrogen exposure with subsequent development of precancerous lesions (endometrial intraepithelial hyperplasia-EIN/atypical hyperplasia), are associated with frequent PTEN inactivation mutations, and have a favorable outcome. 1,2 By contrast, Type II tumors demonstrate papillary serous or clear cell morphology, are not associated with any known precursor lesions, demonstrate frequent p53 mutations, and are associated with a poor outcome. 3,4 The differences between these groups are summarized in Table 1. The observation that uterine papillary serous carcinomas have a greater tendency to metastasis and/ or recurrence in the peritoneum underscores the importance of accurate diagnosis. 5 Although the distinction between serous and endometrioid subgroups of endometrial cancer has a strong theoretical basis, subsets of endometrial adenocarcinoma have been recognized that do not fall cleanly into either of the two categories. Tumors with glandular architecture that more closely approximate endometrioid adenocarcinoma may occasionally demonstrate...

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Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers

Cited by 759 publications

References 22 publications

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

The Akt pathway in human breast cancer: a tissue-array-based analysis

Histologic and immunohistochemical decision-making in endometrial adenocarcinoma

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