Activated Mutant p110α Causes Endometrial Carcinoma in the Setting of Biallelic Pten Deletion
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Abstract:
PTEN and PIK3CA mutations occur with high frequency in uterine endometrioid carcinoma (UEC). Although PTEN mutations are present in complex atypical hyperplasia and carcinoma, PIK3CA mutations are restricted to carcinoma. We generated mouse models harboring Pten loss and/or activated Pik3ca in the endometrial epithelium to investigate their respective roles in the pathogenesis of UEC. Presence of an activated mutant Pik3ca on the background of Pten loss led to aggressive disease, with 100% of mice exhibiting carcinoma. Expression of Pik3ca with E545K mutation alone was unable to cause hyperplasia or cancer in the uterus and did not activate Akt as effectively as Pten deletion in short-term cultures of mouse endometrial epithelium, likely explaining the lack of phenotype in vivo. We also report that nuclear localization of FOXO1 correlated with PTEN mutational status irrespective of the PIK3CA status in endometrial cancer cell lines. Furthermore, gene expression profiles resulting from Pten loss or activation of Pik3ca in primary mouse endometrial epithelial cells exhibit minimal overlap. Thus, Pten and Pik3ca have distinct consequences on the activation of the phosphatidylinositol 3-kinase pathway in endometrial epithelium and are likely to affect other nonoverlapping cellular mechanisms involved in the development and progression of the most common type of uterine cancer.Keywords:
Endometrial hyperplasia
P110α
Research dealing with the association between estrogens and endometrial cancer is discussed in this editorial. Three major areas of research are considered: 1) the relationship between endogenous estrogens and endometrial cancer; 2) endometrial cancers produced in experimental animal studies; and 3) the relationship between exogenous estrogens and endometrial cancer in humans. The possibility that endometrial cancer is the final stage of a disruption in endocrine homeostasis is also considered; it is known that continuous, uninterrupted stimulation of estrogen activity causes endometrial hyperplasia, and it is possible that in some cases this may progress to a malignant process. The author concludes that the use of exogenous estrogen preparations presents an increased risk of endometrial cancer only when they have been used for a long duration, such as 5 or 10 years on a continuous basis. He suggests that if a woman accepts the possible risk of developing endometrial hyperplasia, the gynecologist must accept responsibility for prescribing the smallest dose of estrogen which is appropriate, and for stopping estrogen therapy as soon as any hyperplastic changes are observed in the endometrium.
Endometrial hyperplasia
Atypical Hyperplasia
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Abstract The phosphatidylinositol 3′-kinase (PI3K) pathway is activated in many human cancers. In addition to inactivation of the PTEN tumor suppressor gene, mutations or amplifications of the catalytic subunit α of PI3K (PIK3CA) have been reported. However, the coexistence of mutations in these two genes seems exceedingly rare. As PTEN mutations occur at high frequency in endometrial carcinoma, we screened 66 primary endometrial carcinomas for mutations in the helical and catalytic domains of PIK3CA. We identified a total of 24 (36%) mutations in this gene and coexistence of PIK3CA/PTEN mutations at high frequency (26%). PIK3CA mutations were more common in tumors with PTEN mutations (17 of 37, 46%) compared with those without PTEN mutations (7 of 29, 24%). Array comparative genomic hybridization detected 3q24-qter amplification, which covers the PIK3CA gene (3q26.3), in one of nine tumors. Knocking down PTEN expression in the HEC-1B cell line, which possesses both K-Ras and PIK3CA mutations, further enhances phosphorylation of Akt (Ser473), indicating that double mutation of PIK3CA and PTEN has an additive effect on PI3K activation. Our data suggest that the PI3K pathway is extensively activated in endometrial carcinomas, and that combination of PIK3CA/PTEN alterations might play an important role in development of these tumors.
P110α
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Significance Aberrant activation of the PI3K pathway is a frequent event in human cancer, making PI3K an attractive target in cancer therapy. Early generation inhibitors have poor efficacy and intolerable side effects; new PI3K isoform-selective inhibitors are emerging in the clinic. Much work is ongoing to determine the isoform dependence of different cancers. Of the ubiquitously expressed isoforms, p110α is critical for activated receptor tyrosine kinases or oncogenes, whereas p110β seems essential in many tumors deficient of the phosphatase and tensin homolog (PTEN). We show for the first time, to our knowledge, that PTEN-null ovarian tumors requiring p110β can become dependent on p110α through concurrent activation of the rat sarcoma protein Kras G12D . Our results provide critical insights into patient selection and stratification in current and future clinical trial designs with PI3K inhibitors.
Tensin
P110α
Phosphoinositide 3-kinase
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Endometrial hyperplasia
Atypia
Atypical Hyperplasia
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Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 1980-2003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 1980-1990, -12.9% (95% CI = -15.6% to -10.1%) for 1990-1999 and 2.4% (95% CI = -6.6% to 12.2%) for 1999-2003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 1980-2000 and 24.5% (95% CI = -16.5% to 85.7%) for 2000-2003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 1980-1988 and 1.4% (95% CI = -0.2% to 3.0%) for 1988-2003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia.
Endometrial hyperplasia
Uterine cancer
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Purpose: To evaluate the effect of age on prediction of concurrent endometrial cancer (EC) in patients with atypical endometrial hyperplasia (AEH). Materials and Methods: Medical data of 176 patients who were diagnosed with atypical endometrial hyperplasia and underwent surgical treatment enrolled the study group. Clinicopathological features, preoperative and postoperative information were collected. The age distrubition for patients with atypical endometrial hyperplasia and endometrial cancer were examined and stratified according to five-year age increments. Results: Concurrent endometrial cancer was detected in 35(19.8%) patients. atypical endometrial hyperplasia and lower grade hyperplasia (simple or complex) was found in 82(46.5%) and 27(15.3%) patients, respectively. Endometrial cancer was most frequently seen in 51-60 age group. Endometrial cancer in final pathology significantly increased (p = 0,0005) after the age of 53 with sensitivity of 65.52% and 76.67%. Conclusion: Endometrial cancer increases significantly after the age of 53 in patients with atypical endometrial hyperplasia. Based on this study it is recommended that clinicians shoud be aware of this knowledge while informing patients and planning treatment.
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Atypical Hyperplasia
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Objective: To explore the expression of PTEN and MTA1 and their correlation in the endometrial cancer.Methods: In 130 cases of endometrial cancer and 40 cases of normal endometrial,the expression of PTEN and MTA1 was examined with immunohis-tochemistry SP method and their correlation.Results: The expression of PTEN and MTA1 in endometrial cancer was higher than that in normal endometrial.(P0.01).PTEN expression levels in endometrial cancer were inversely correlated with MTA1 protein.(r=-0.35,P0.05).Conclusion: Expression of PTEN expression and MTA1 is inversely correlated with the development and progression of en-dometrial cancer.
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The PI3K (phosphoinositide 3-kinase) pathway is commonly activated in cancer as a consequence of inactivation of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K signalling. In line with this important role of PTEN, mice that are heterozygous for a PTEN-null allele (PTEN+/− mice) spontaneously develop a variety of tumours in multiple organs. PTEN is a phosphatase with selectivity for PtdIns(3,4,5)P3, which is produced by the class I isoforms of PI3K (p110α, p110β, p110γ and p110δ). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110β, and that p110β, but not p110α, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110α can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110α- or p110β-selective inhibitors, we confirm that inactivation of p110β, but not p110α, inhibits prostate cancer development in PTEN+/− mice, but also find that p110α inactivation protects from glomerulonephritis, pheochromocytoma and thyroid cancer induced by PTEN loss. This indicates that p110α can modulate the impact of PTEN loss in disease and tumourigenesis. In primary and immortalized mouse fibroblast cell lines, both p110α and p110β controlled steady-state PtdIns(3,4,5)P3 levels and Akt signalling induced by heterozygous PTEN loss. In contrast, no correlation was found in primary mouse tissues between PtdIns(3,4,5)P3 levels, PI3K/PTEN genotype and cancer development. Taken together, our results from the present study show that inactivation of either p110α or p110β can counteract the impact of PTEN inactivation. The potential implications of these findings for PI3K-targeted therapy of cancer are discussed.
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P110α
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Loss of PTEN, the negative regulator of PI3K activity, is frequent in glioblastomas (GBMs). However, the role of the two major PI3K isoforms, p110α and p110β, in PTEN-deficient gliomagenesis remains unknown. We show that PTEN-deficient GBM largely depends on p110α for proliferation and p110β for migration. Genetic ablation of either isoform delays tumor progression in mice, but only ablating both isoforms completely blocks GBM driven by the concurrent ablation of Pten and p53. BKM120 (buparlisib) treatment only modestly prolongs survival in mice bearing intracranial Pten/p53 null tumors due to partial pathway inhibition. BKM120 extends the survival of mice bearing intracranial tumors in which p110β, but not p110α, has been genetically ablated in the Pten/p53 null glioma, indicating that BKM120 fails to inhibit p110β effectively. Our study suggests that the failure of PI3K inhibitors in GBM may be due to insufficient inhibition of p110β and indicates a need to develop brain-penetrant p110α/β inhibitors.
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