PTEN; phosphatase and tensin homolog (10q23.3)

Gene Summary

Gene:PTEN; phosphatase and tensin homolog
Aliases: BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del
Summary:This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
Updated:12 July, 2014


What does this gene/protein do?
PTEN is implicated in:
- activation of mitotic anaphase-promoting complex activity
- anaphase-promoting complex binding
- angiogenesis
- apoptotic process
- brain morphogenesis
- canonical Wnt receptor signaling pathway
- cardiac muscle tissue development
- cell migration
- cell projection
- cell proliferation
- central nervous system development
- central nervous system myelin maintenance
- central nervous system neuron axonogenesis
- cytoplasm
- cytosol
- dendritic spine morphogenesis
- dentate gyrus development
- endothelial cell migration
- enzyme binding
- epidermal growth factor receptor signaling pathway
- fibroblast growth factor receptor signaling pathway
- forebrain morphogenesis
- heart development
- induction of apoptosis
- inositol phosphate dephosphorylation
- inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity
- internal side of plasma membrane
- learning or memory
- lipid binding
- locomotor rhythm
- locomotory behavior
- long-term synaptic potentiation
- magnesium ion binding
- male mating behavior
- maternal behavior
- multicellular organismal response to stress
- myelin sheath adaxonal region
- negative regulation of apoptotic process
- negative regulation of axonogenesis
- negative regulation of cell aging
- negative regulation of cell migration
- negative regulation of cell proliferation
- negative regulation of cell size
- negative regulation of cyclin-dependent protein kinase activity involved in G1/S
- negative regulation of dendritic spine morphogenesis
- negative regulation of epithelial cell proliferation
- negative regulation of excitatory postsynaptic membrane potential
- negative regulation of focal adhesion assembly
- negative regulation of G1/S transition of mitotic cell cycle
- negative regulation of myelination
- negative regulation of organ growth
- negative regulation of phosphatidylinositol 3-kinase cascade
- negative regulation of protein kinase B signaling cascade
- negative regulation of protein phosphorylation
- negative regulation of ribosome biogenesis
- negative regulation of synaptic vesicle clustering
- nerve growth factor receptor signaling pathway
- neuron projection
- neuron-neuron synaptic transmission
- nucleus
- PDZ domain binding
- peptidyl-tyrosine dephosphorylation
- phosphatidylinositol biosynthetic process
- phosphatidylinositol dephosphorylation
- phosphatidylinositol-3-phosphatase activity
- phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity
- phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
- phosphatidylinositol-mediated signaling
- phospholipid metabolic process
- phosphoprotein phosphatase activity
- plasma membrane
- PML body
- positive regulation of cell proliferation
- positive regulation of excitatory postsynaptic membrane potential
- positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process
- positive regulation of sequence-specific DNA binding transcription factor activity
- postsynaptic density assembly
- prepulse inhibition
- presynaptic membrane assembly
- prostate gland growth
- protein binding
- protein dephosphorylation
- protein kinase B signaling cascade
- protein kinase binding
- protein serine/threonine phosphatase activity
- protein stabilization
- protein tyrosine phosphatase activity
- protein tyrosine/serine/threonine phosphatase activity
- regulation of B cell apoptotic process
- regulation of cellular component size
- regulation of cyclin-dependent protein kinase activity
- regulation of myeloid cell apoptotic process
- regulation of neuron projection development
- regulation of protein stability
- rhythmic synaptic transmission
- Schmidt-Lanterman incisure
- small molecule metabolic process
- social behavior
- synapse assembly
- synapse maturation
- T cell receptor signaling pathway
Data from Gene Ontology via CGAP


What pathways are this gene/protein implicaed in?
- mTOR Signaling Pathway BIOCARTA
- PTEN dependent cell cycle arrest and apoptosis BIOCARTA
- Regulation of eIF4e and p70 S6 Kinase BIOCARTA
- Signaling of Hepatocyte Growth Factor Receptor BIOCARTA
- Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway BIOCARTA
- Focal adhesion KEGG
- Inositol phosphate metabolism KEGG
- Phosphatidylinositol signaling system KEGG
- Tight junction KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

As tumours progress to more advanced stages, they tend to acquire an increasing number of genetic alterations. One common alteration seen in a range of different advanced cancers is mutation of the PTEN gene, a gene which is linked with cell regulation and apoptosis (programmed cell death). Mutations in the PTEN gene are documented in cancers of the breast, prostate, endometrium, ovary, colon, melanoma, glioblastoma. and lymphoma. Animal models have shown that the loss of just one copy of the PTEN gene is enough to interrupt cell signalling and begin the process of uncontrolled cell growth. However, the significance of PTEN alterations in carcinogenesis is controversial since aberrant transcripts of PTEN have also been identified in normal non-cancerous tissues.

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 July 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 12 July, 2014 using data from PubMed, MeSH and CancerIndex


PTEN mutations in Endometrial Cancer
Mutations of the PTEN suppressor gene are the most frequent genetic abnormality in endometrial cancers. They occur in 40-80% of endometrioid carcinomas, which account for the majority of endometrial cancers. PTEN mutations have also been detected in the precancerous condition endometrial intraepithelial neoplasia.
Related Publications (408)

PTEN and Astrocytoma

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PTEN and Glioblastoma

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PTEN and Prostate Cancer

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PTEN and Lung Cancer

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PTEN and Thyroid Cancer

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PTEN and Stomach Cancer

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PTEN in Precancerous Conditions
PTEN mutations are implicated in a number of precancerous conditions. For example Mutter and colleagues (JNCI, 2000) found 16/29 (55%) of endometrial intraepithelial neoplasia (a precancerous condition) had PTEN mutations compared to 25/30 (83%) of endometrioid adenocarcinomas. They suggest that PTEN may be a useful immunohistochemical biomarker for premalignant disease. The precancers were characterised by mutation of only 1 PTEN allele while the adenocarcinomas showed reduced or complete loss of PTEN protein expression.
Related Publications (50)

PTEN and Soft Tissue Sarcoma

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PTEN and Testicular Cancer

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PTEN Amplification in Ewing's Sarcoma?
In a genome-wide copy-number analysis of Ewing's sarcoma, Lynn et al (2013) found localized copy-number alterations of PTEN.
Related Publications (1)

Related Links

Latest Publications: PTEN (cancer-related)

Seewaldt V
ECM stiffness paves the way for tumor cells.
Nat Med. 2014; 20(4):332-3 [PubMed] Related Publications

Kovalenko TF, Sorokina AV, Ozolinia LA, Patrushev LI
[Pseudogene PTENP1 5'-region methylation in endometrial cancer and hyperplasias].
Bioorg Khim. 2013 Jul-Aug; 39(4):445-53 [PubMed] Related Publications
Genetic mutations in tumor suppressor gene PTEN are often detected in malignant human cells and these genomic changes are especially characteristic ofendometrial cancer. In our previous researches we assumed that alternative epigenetic mechanism of PTEN inactivation trough promoter methylation may exist in endometrial cancer. Moreover, PTENP1 pseudogene has recently been shown to play a role in positive regulation of PTENgene expression. Taking into account these facts, we analyzed PTEN and PTENP1 methylation status in endometrial hyperplasia and cancer. It was demonstrated that PTENgene promoter was not methylated but PTENP1 was methylated in 11 of 18 endometrial cancers and in 5 of9 endometrial hyperplasias. We can assume that PTENP1 methylation may inhibit transcription of this gene and also PTEN gene transcription trough RNA interference in accordance with ceRNA theory. Thus, aberrant suppression of PTENP1 transcription can play a role in endometrial cancer pathogenesis.

Related: Endometrial (Uterus) Cancer Endometrial Cancer

Gupta C, Kaur J, Tikoo K
Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions.
Exp Cell Res. 2014; 324(1):75-83 [PubMed] Related Publications
Hyperglycemia is a critical risk factor for development and progression of breast cancer. We have recently reported that high glucose induces phosphorylation of histone H3 at Ser 10 as well as de-phosphorylation of GSK-3β at Ser 9 in MDA-MB-231 cells. Here, we elucidate the mechanism underlying hyperglycemia-induced proliferation in MDA-MB-231 breast cancer cells. We provide evidence that hyperglycemia led to increased DNA methylation and DNMT1 expression in MDA-MB-231 cells. High glucose condition led to significant increase in the expression of PCNA, cyclin D1 and decrease in the expression of PTPN 12, p21 and PTEN. It also induced hypermethylation of DNA at the promoter region of PTPN 12, whereas hypomethylation at Vimentin and Snail. Silencing of GSK-3β by siRNA prevented histone H3 phosphorylation and reduced DNMT1 expression. We show that chromatin obtained after immunoprecipitation with phospho-histone H3 was hypermethylated under high glucose condition, which indicates a cross-talk between DNA methylation and histone H3 phosphorylation. ChIP-qPCR analysis revealed up-regulation of DNMT1 and metastatic genes viz. Vimentin, Snail and MMP-7 by phospho-histone H3, which were down-regulated upon GSK-3β silencing. To the best of our knowledge, this is the first report which shows that interplay between GSK-3β activation, histone H3 phosphorylation and DNA methylation directs proliferation of breast cancer cells.

Related: Breast Cancer

Kim SY, Hong C, Wie J, et al.
Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells.
Biochem Biophys Res Commun. 2014; 447(1):192-6 [PubMed] Related Publications
Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB-TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6-NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB-TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex.

Related: Prostate Cancer Signal Transduction

Serizawa M, Koh Y, Kenmotsu H, et al.
Assessment of mutational profile of Japanese lung adenocarcinoma patients by multitarget assays: a prospective, single-institute study.
Cancer. 2014; 120(10):1471-81 [PubMed] Related Publications
BACKGROUND: Integration of mutational profiling to identify driver genetic alterations in a clinical setting is necessary to facilitate personalized lung cancer medicine. A tumor genotyping panel was developed and the Shizuoka Lung Cancer Mutation Study was initiated as a prospective tumor genotyping study. This study reports the frequency of driver genetic alterations in Japanese lung adenocarcinoma patients, and clinicopathologic correlations with each genotype.
METHODS: Between July 2011 and January 2013, 411 lung adenocarcinoma patients admitted to the Shizuoka Cancer Center were included in this study with their written informed consent. Surgically resected tissues, tumor biopsies, and/or body cavity fluids were collected and tested for 23 hotspot sites of driver mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene amplifications in 5 genes (EGFR, MET, PIK3CA, FGFR1, and FGFR2), and ALK, ROS1, and RET fusions.
RESULTS: Genetic alterations were detected in 54.3% (223 of 411) of all patients. The most common genetic alterations detected in this study were EGFR mutations (35.0%) followed by KRAS mutations (8.5%) and ALK fusions (5.0%). Concurrent genetic alterations were detected in 22 patients (5.4%), and EGFR mutations were observed in 16 patients as the most common partner for concurrent genetic alteration. Significantly more concurrent genetic alterations were observed in older patients.
CONCLUSIONS: This is one of the largest reports of a prospective tumor genotyping study on Japanese patients with adenocarcinoma. These data suggest that mutational profiling data using a multimutational testing platform would be valuable for expanding the range of molecular-targeted therapeutics in lung cancer.

Related: Lung Cancer KRAS gene EGFR

Wei Z, Cui L, Mei Z, et al.
miR-181a mediates metabolic shift in colon cancer cells via the PTEN/AKT pathway.
FEBS Lett. 2014; 588(9):1773-9 [PubMed] Related Publications
Cancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetics pathway, a phenomenon known as the warburg effect. Whether the deregulation of miRNAs contributes to the warburg effect remains largely unknown. Here we show that miR-181a expression is increased and thus induces a metabolic shift in colon cancer cells. miR-181a performs this function by inhibiting the expression of PTEN, leading to an increase of phosphorylated AKT which triggers metabolic shift. The increase of lactate production induced by miR-181a results in the rapid growth of cancer cells. These results identify miR-181a as a molecular switch involved in the orchestration of the warburg effect in colon cancer cells via the PTEN/AKT pathway.

Related: AKT1 Signal Transduction

Garcia AJ, Ruscetti M, Arenzana TL, et al.
Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression.
Mol Cell Biol. 2014; 34(11):2017-28 [PubMed] Article available free on PMC after 01/12/2014 Related Publications
Chronic inflammation is known to be associated with prostate cancer development, but how epithelium-associated cancer-initiating events cross talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1(+) CD11b(+) cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities. Treatment of Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor-initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression.

Related: Prostate Cancer Signal Transduction

Li L, Zhou L, Li Y, et al.
MicroRNA-21 stimulates gastric cancer growth and invasion by inhibiting the tumor suppressor effects of programmed cell death protein 4 and phosphatase and tensin homolog.
J BUON. 2014 Jan-Mar; 19(1):228-36 [PubMed] Related Publications
PURPOSE: MicroRNA-21 (miR-21) is abnormally expressed in many solid cancers, such as gastric adenocarcinoma, and regulates some targets involved in cancer initiation and progression. In this study, we investigated the function of miR-21 in two gastric cancer cell lines, as well as its potential targeting of the tumor suppressor genes phosphatase and tensin homolog (PTEN) and programmed cell death protein 4 (PDCD4).
METHODS: The first step was to use quantitative (q) RTPCR in order to verify the overexpression of miR-21 in two different gastric cancer cell lines (SGC-7901 and MKN-45) transfected with mIR-21 mimic. Western blotting confirmed the qRT-PCR data in a set of rescue experiments in which miR-21 mimic, inhibitor, and non specific mimic (NSM) were used to transfect the two gastric cancer cell lines. The protein levels of miR-21 targets PTEN and PDCD4 were estimated. Then, we evaluated its effect on tumor growth and invasion potential on the two different gastric adenocarcinoma cell lines.
RESULTS: qRT-PCR results proved that miR-21 was overexpressed in gastric cancer cells transfected with miR-21 mimic. Western blot results further suggested that PTEN and PDCD4 were regulated by miR-21, as miR-21 inhibitor increased the expression of PTEN and PDCD4 proteins and significantly reduced cell proliferation, migration and invasion. In the control experiment miR-21 mimic significantly inhibited the expression of PTEN and PDCD4 proteins in the two gastric cell lines, leading to an increase in cell invasion and migration. Furthermore, miR-21 mimic inhibited the apoptosis of the two gastric cancer cell lines.
CONCLUSIONS: miR-21 is overexpressed in gastric cancer and its aberrant expression may have important role in gastric cancer growth and dissemination by modulating the expression of the tumor suppressors PTEN and PDCD4, as well as by modulating the pathways involved in mediating cell growth, migration, invasion and apoptosis. Targeting miR-21 may help develop novel therapeutics for gastric cancer, once its pathophysiology is completely investigated.

Related: Apoptosis Stomach Cancer Gastric Cancer miR-21 PDCD4

Mouw JK, Yui Y, Damiano L, et al.
Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.
Nat Med. 2014; 20(4):360-7 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.

Related: Breast Cancer HOXA9 gene

Melchor L, Molyneux G, Mackay A, et al.
Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models.
J Pathol. 2014; 233(2):124-37 [PubMed] Related Publications
The heterogeneous nature of mammary tumours may arise from different initiating genetic lesions occurring in distinct cells of origin. Here, we generated mice in which Brca2, Pten and p53 were depleted in either basal mammary epithelial cells or luminal oestrogen receptor (ER)-negative cells. Basal cell-origin tumours displayed similar histological phenotypes, regardless of the depleted gene. In contrast, luminal ER-negative cells gave rise to diverse phenotypes, depending on the initiating lesions, including both ER-negative and, strikingly, ER-positive invasive ductal carcinomas. Molecular profiling demonstrated that luminal ER-negative cell-origin tumours resembled a range of the molecular subtypes of human breast cancer, including basal-like, luminal B and 'normal-like'. Furthermore, a subset of these tumours resembled the 'claudin-low' tumour subtype. These findings demonstrate that not only do mammary tumour phenotypes depend on the interactions between cell of origin and driver genetic aberrations, but also multiple mammary tumour subtypes, including both ER-positive and -negative disease, can originate from a single epithelial cell type. This is a fundamental advance in our understanding of tumour aetiology.

Related: Breast Cancer TP53

Kechagioglou P, Papi RM, Provatopoulou X, et al.
Tumor suppressor PTEN in breast cancer: heterozygosity, mutations and protein expression.
Anticancer Res. 2014; 34(3):1387-400 [PubMed] Related Publications
Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is one of the most frequently mutated human tumor suppressor genes, implicated in cell growth and survival and suppressing tumor formation. Loss of PTEN activity, either at the protein or genomic level, has been related to many primary and metastatic malignancies including breast cancer. The present study investigates the heterozygosity, mutation spectrum and protein expression of PTEN in 43 patients with breast cancer or precursor lesions of the breast and 10 healthy individuals. Microsatellite analysis at the PTEN locus using D10S215, D10S541 and D10S579 markers indicated that the observed heterozygosity (Ho) is lower than the expected heterozygosity (Hs) in benign and malignant breast disease. Mutational analysis in exons 1, 5, 7 and 9 of the PTEN gene revealed several mutations, most of which cause truncation of the PTEN protein and consequently loss of activity. Increased circulating levels of PTEN and phosphorylated PTEN protein were also observed by immunostaining in patients with breast cancer and precursor breast lesions. In support, increased PTEN protein expression was detected in corresponding tissue specimens. Our data suggest an association between breast cancer and PTEN mutations, resulting in the production of truncated forms of the corresponding protein, thus indicating that breast carcinogenesis is potentially related to PTEN loss of activity rather than loss of expression. Peripheral blood sampling may provide an advantageous application for the determination of PTEN gene mutations and its protein expression in human cancer.

Related: Breast Cancer Chromosome 10

Razis E, Pentheroudakis G, Rigakos G, et al.
EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab.
J Cancer Res Clin Oncol. 2014; 140(5):737-48 [PubMed] Related Publications
INTRODUCTION: Cetuximab is a monoclonal epidermal growth factor receptor (EGFR)-targeting antibody, used in the treatment of colon cancer. KRAS mutation status is strongly predictive of cetuximab efficacy, but more predictive factors are needed for better patient selection. PTEN is a downstream inhibitor of the EGFR pathway and has been evaluated as a predictive factor of cetuximab efficacy in colorectal cancer.
PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tumor tissue samples were collected from 226 patients with advanced or metastatic colorectal cancer that had been treated with cetuximab. Clinical information was collected retrospectively from the patients' medical records. After central evaluation, 147 cases with adequate material were eligible for further evaluation. EGFR and PTEN status was evaluated with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Data were associated with cetuximab treatment outcome. Additional analysis was performed with previously published data on PIK3CA, BRAF and KRAS mutation status and EGFR ligand amphiregulin (AREG) and epiregulin intratumoral mRNA expression levels. PIK3CA mutation status and PTEN protein expression were also analyzed as a single complex parameter, to evaluate the predictive value of PI3K/PTEN axis dysfunction as one entity.
RESULTS: Analysis showed a borderline association of overall response rate (ORR) and time to progression (TTP) with EGFR protein overexpression by IHC (p = 0.059 and p = 0.057, respectively) and a positive association of EGFR gain by FISH (found in only five cases) with longer TTP (p = 0.026). No association was found between ORR or TTP and PTEN IHC or FISH status. Comparative analysis with previously published data showed that PTEN protein expression is associated with longer TTP in patients with wild-type (WT) KRAS (p = 0.036) and especially in the ones with elevated AREG levels (p = 0.046), as well as in patients with both KRAS and BRAF WT (p = 0.019). Patients with both PIK3CA WT and PTEN protein expression had significantly longer TTP (p = 0.010) versus all others, in the absence of BRAF and KRAS mutations, a finding which persisted in the KRAS WT/AREG high subgroup (p = 0.046).
CONCLUSIONS: In this cetuximab-treated colorectal cancer population, EGFR gain was associated with better outcome and PTEN protein expression with longer TTP in KRAS WT, KRAS WT/AREG high and KRAS/BRAF WT subpopulations. Cetuximab efficacy is greater with intact and activated EGFR signaling, without activating mutations of KRAS/BRAF and in the presence of preserved PTEN inhibitory activity upon the PI3K/AKT pathway. These results reflect a solid biological rationale and warrant further evaluation of the predictive role of PTEN in prospective studies.

Related: Colorectal (Bowel) Cancer KRAS gene EGFR Cetuximab (Erbitux)

Tural D, Serdengecti S, Demirelli F, et al.
Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.
Br J Cancer. 2014; 110(8):1968-76 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ~30-40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively.
MATERIALS AND METHODS: Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ(2), Fischer's exact test and Mann-Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and survival curves of subgroups were compared with log-rank test.
RESULTS: Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5-13.4 months) and 22 months (95% CI, 9.9-34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6-34 months) and 12.1 months (95% CI, 7.9-16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3-40.4 months) and 29.1 months (95% CI, 8.6-43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5-40.1 months) and 26.8 months (95% CI, 8.1-42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2-4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1-3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18-4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14-3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis.
CONCLUSIONS: Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.

Related: Breast Cancer AKT1 VAV1 Trastuzumab (Herceptin)

Otterstrom C, Soltermann A, Opitz I, et al.
CD74: a new prognostic factor for patients with malignant pleural mesothelioma.
Br J Cancer. 2014; 110(8):2040-6 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: The pro-inflammatory cytokine migration inhibitory factor (MIF) and its receptor CD74 have been proposed as possible therapeutic targets in several cancers. We studied the expression of MIF and CD74 together with calretinin in specimens of malignant pleural mesothelioma (MPM), correlating their expression levels with clinico-pathologic parameters, in particular overall survival (OS).
METHODS: Migration inhibitory factor, CD74, and calretinin immunoreactivity were investigated in a tissue microarray of 352 patients diagnosed with MPM. Protein expression intensities were semiquantitatively scored in the tumour cells and in the peritumoral stroma. Markers were matched with OS, age, gender, and histological subtype.
RESULTS: Clinical data from 135 patients were available. Tumour cell expressions of MIF and CD74 were observed in 95% and 98% of MPM specimens, respectively, with a homogenous distribution between the different histotypes. CD74 (P<0.001) but not MIF overexpression (P=0.231) emerged as an independent prognostic factor for prolonged OS. High expression of tumour cell calretinin correlated with the epithelioid histotype and was also predictive of longer OS (P<0.001). When compared with previously characterised putative epithelial-to-mesenchymal transition markers, CD74 correlated positively with tumoral PTEN and podoplanin expressions, but was inversely related with periostin expression.
CONCLUSIONS: High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.

Related: Lung Cancer Mesothelioma CD74 gene MIF

Bradford LS, Rauh-Hain A, Clark RM, et al.
Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer.
Gynecol Oncol. 2014; 133(2):346-52 [PubMed] Related Publications
OBJECTIVE: Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model.
METHODS: NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C+BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation.
RESULTS: In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p<0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p<0.05). Synergistic tumor growth suppression (p<0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels.
CONCLUSION: Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.

Related: Carboplatin Endometrial (Uterus) Cancer Endometrial Cancer Paclitaxel AKT1 Signal Transduction

Stelloo E, Nout RA, Naves LC, et al.
High concordance of molecular tumor alterations between pre-operative curettage and hysterectomy specimens in patients with endometrial carcinoma.
Gynecol Oncol. 2014; 133(2):197-204 [PubMed] Related Publications
OBJECTIVE: Molecular alterations in endometrial cancer have been shown to be prognostically significant but have not yet been implemented in the current clinical risk assessment. Few studies have investigated the reliability of molecular alterations in pre-operative specimens. Therefore, the objective was to determine whether molecular analysis of pre-operative endometrial cancer samples accurately reflects those alterations in the subsequent hysterectomy specimens.
METHODS: Paired pre-operative and hysterectomy specimens of 48 patients diagnosed with endometrial carcinoma, 42 endometrioid (EEC) and 6 non-endometrioid (NEEC) carcinomas, were analyzed for immunohistochemical expression of p53, PTEN and β-catenin. Tumor DNA was isolated and analyzed for microsatellite instability (MSI), TP53 mutations and somatic hot spot mutations in 13 genes.
RESULTS: In EEC patients, loss of PTEN, nuclear β-catenin and p53-mutant expression was found in 43%, 7% and 12%, respectively. No nuclear β-catenin was found in 5 of 6 NEEC patients, all serous cancers, whereas a p53-mutant expression was present in all serous cases. MSI was found in 19.5%, all EEC. Concordance for PTEN, β-catenin, p53 expression and MSI status was found in 79%, 92%, 79% and 93.5%, respectively. We detected 65 hot spot mutations in 39/48 (81%) tumors. Overall concordance of the GynCarta multigene analysis was 99.8%.
CONCLUSIONS: The results confirm the reliability of immunohistochemical and DNA-based techniques in the evaluation of molecular alterations in pre-operative endometrial specimens and high concordance rates with the definitive hysterectomy specimens. The resulting molecular signature provides initial pre-operative diagnostic information on the status of oncogenic pathways, which may contribute to individualized treatment strategies.

Related: Endometrial (Uterus) Cancer Endometrial Cancer TP53

Pringle DR, Vasko VV, Yu L, et al.
Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice.
J Clin Endocrinol Metab. 2014; 99(5):E804-12 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
CONTEXT: Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC.
OBJECTIVE: The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC.
DESIGN: We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors.
SETTING: The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals. Patients: Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases. Interventions: There were no interventions.
MAIN OUTCOME MEASURES: Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression.
RESULTS: Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement.
CONCLUSIONS: These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.

Related: Signal Transduction Thyroid Cancer

Wachsberger PR, Lawrence YR, Liu Y, et al.
Hsp90 inhibition enhances PI-3 kinase inhibition and radiosensitivity in glioblastoma.
J Cancer Res Clin Oncol. 2014; 140(4):573-82 [PubMed] Related Publications
PURPOSE: Combined targeting with a PI3-kinase inhibitor, BKM120, and an Hsp90 inhibitor, HSP990, was investigated as a multi-targeted approach to potentiate cell death in glioblastoma (GBM). Additionally, the effect of dual drug treatment combined with cytotoxic stress (radiation therapy) was examined.
METHODS: Four human GBM cell lines containing wild-type or mutated PTEN and/or p53 were studied. The effects of drug treatments on cell viability, apoptosis induction, pAKt activity, cell cycle arrest, clonogenicity, and tumor growth delay were studied.
RESULTS: Combined concurrent treatment with both drugs produced more cell killing in cell viability and apoptosis assays than either drug alone. BKM120 plus HSP990 induced suppression of baseline Akt signaling as well as radiation (RT)-induced pAkt signaling in all cell lines. Cell cycle analysis revealed that HSP990 and BKM120, singly or combined, induced G2/M arrest leading to apoptosis/necrosis and polyploidy. Additionally, the drugs radiosensitized GBM cells in clonogenic assays. In vivo tumor growth delay studies demonstrated the effectiveness of combined drug treatment with HSP990 and BKM120 over single drug treatment, as well as the effectiveness of combined drug treatment in enhancing the effectiveness of radiation therapy.
CONCLUSIONS: In conclusion, HSP990 and BKM120, with and without RT, are active agents against glioma tumors. The sensitivity to these agents does not appear to depend on PTEN/p53status in the cell lines tested. We suggest that the combined action of both drugs is a viable multi-targeted strategy with the potential to improve clinical outcome for patients with high-grade glioma.

Related: Apoptosis

Ding L, Chen S, Liu P, et al.
CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy.
Cancer Res. 2014; 74(7):2050-61 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbp(pc-/-);Pten(pc+/-) mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp(-/-); Pten(+/-) and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27(KIP1), and p21(CIP1). Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbp(pc-/-);Pten(pc+/-) mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer.

Related: Prostate Cancer AKT1

Zhong J, Ding L, Bohrer LR, et al.
p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis.
Cancer Res. 2014; 74(6):1870-80 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion-induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference-mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss.

Related: Prostate Cancer

Santoni M, Pantano F, Amantini C, et al.
Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma.
Biochim Biophys Acta. 2014; 1845(2):221-31 [PubMed] Related Publications
The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. Unfortunately, a number of potential mechanisms that may lead to resistance to mTOR inhibitors have been proposed. In this paper, we discuss the mechanisms underlying resistance to mTOR inhibitors, which include the downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, the activation of hypoxia-inducible factor (HIF), the PIM kinase family, PTEN expression, elevated superoxide levels, stimulation of autophagy, immune cell response and ERK/MAPK, Notch and Aurora signaling pathways. Moreover, we present an updated analysis of clinical trials available on PubMed Central and www.clinicaltrials.gov, which were pertinent to the resistance to rapalogs. The new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and cross talks with other pathways involved in the acquired resistance to mTOR inhibitors. The true goal will be to identify biomarkers predictive of sensitivity or resistance to efficiently develop novel agents with the aim to avoid toxicities and to better choose the active drug for the right patient.

Related: AKT1 Signal Transduction Temsirolimus (Torisel) Everolimus (Afinitor)

Klein P, Müller-Rischart AK, Motori E, et al.
Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants.
EMBO J. 2014; 33(4):341-55 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (Ret(MEN₂B) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret(MEN₂B) significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD.

Related: Apoptosis Neuroblastoma Signal Transduction

Schmidt JW, Wehde BL, Sakamoto K, et al.
Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis.
Mol Cell Biol. 2014; 34(7):1363-77 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Stat5 (signal transducer and activator of transcription 5) is an essential mediator of cytokine receptor signaling and plays important roles in the proliferation of alveolar progenitors and the survival of functionally differentiated epithelial cells in the mammary gland. A deregulated expression and activation of Stat5 leads to precocious alveolar development in the absence of pregnancy hormones, impaired mammary gland remodeling following the cessation of lactation, and mammary tumor formation. We reported previously that Stat5 induces the transcription of the Akt1 gene from a novel promoter. In this report, we provide experimental evidence that Akt1 is an essential mediator for the biological function of Stat5 as a survival factor. Additionally, Stat5 controls the expression of the regulatory and catalytic subunits of the phosphatidylinositol 3-kinase (PI3K) (p85α and p110α), thereby greatly augmenting signaling through the prosurvival PI3K/Akt pathway. In agreement with this model, we observed that the constitutive activation of Stat5 cooperates with the loss of function of the tumor suppressor PTEN by accelerating the formation of preneoplastic lesions and mammary tumors. The mammary gland-specific ablation of Stat5 is sufficient to prevent mammary carcinogenesis in a genuine mouse model for Cowden syndrome. Therefore, targeting the Jak2/Stat5 pathway might be a suitable strategy to prevent breast cancer in patients that carry a mutant PTEN allele.

Related: AKT1 Signal Transduction

Gao Y, Luo LH, Li S, Yang C
miR-17 inhibitor suppressed osteosarcoma tumor growth and metastasis via increasing PTEN expression.
Biochem Biophys Res Commun. 2014; 444(2):230-4 [PubMed] Related Publications
MicroRNAs (miRNAs) play essential roles in cancer development and progression. Here, we investigated the role of miR-17 in the progression and metastasis of osteosarcoma (OS). miR-17 was frequently increased in OS tissues and cell lines. Inhibition of miR-17 in OS cell lines substantially suppressed cell proliferation, migration, and invasion. Phosphatase and tensin homolog (PTEN) was identified as a target of miR-17, and ectopic expression of miR-17 inhibited PTEN by direct binding to its 3'-untranslated region (3'-UTR). Expression of miR-17 was negatively correlated with PTEN in OS tissues. Together, these findings indicate that miR-17 acts as an oncogenic miRNA and may contribute to the progression and metastasis of OS, suggesting miR-17 as a potential novel diagnostic and therapeutic target of OS.

Related: Osteosarcoma

Zhao H, Wamg Y, He X
[Expression of p-STAT3 in laryngeal squamous carcinoma and its correlation with PTEN].
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2013; 27(18):981-5 [PubMed] Related Publications
OBJECTIVE: To study the expression of p-STAT3 and PTEN in human laryngeal squamous carcinoma, to explore their relations and clinical significance.
METHOD: Formalin-fixed and paraffin-embedded tissues from 67 cases of laryngeal squamous carcinoma, 25 cases of normal mucosa over 2.0 cm away from tumor margin in 25 patients with total or subtotal laryngectomy were evaluated for the expression of p-STAT3, PTEN by SP immunohistochemistry, the levels of these proteins in tissues and their correlation with clinicopathological parameters of laryngeal squamous carcinoma were analyzed. The prognostic analysis was performed by Kaplan-Merier.
RESULT: The expression rates of p-STAT3 protein in laryngeal squamous carcinoma and normal control laryngeal mucous tissues were 71.64%, 16% respectively. There was significant difference between them (Zc = 4.7052, P < 0.01); The expression rates of PTEN protein in laryngeal squamous carcinoma and normal control laryngeal mucous tissues were 41.79%, 96% respectively. There was significant difference between them (Zc = 5.7037, P < 0.01); The expressions of p-STAT3 and PTEN in laryngeal squamous carcinoma were associated with clinical stage, differentiation grade, lymph nodal metastases and prognosis (P < 0.01). There was a negative correlation between the expression of p-STAT3 and PTEN,and their correlation coefficient was r = -0.5148 (P < 0.01). p-STAT3 positive expression rate in patients survived over a 5 years follow up was 56.25% (18/32), which was obviously lower than the rate 82.35% (14/17) in those dead.
CONCLUSION: The expression of p-STAT3 and PTEN may take important roles in the tumorigenesis, aggressiveness, metastases and prognosis of laryngeal squamous carcinoma. The high expression of p-STAT3 was negatively correlated with the lower PTEN in laryngeal squamous carcinoma, which suggested that PTEN may be a downstream target gene of p-STAT3.

Related: Cancer of the Larynx Laryngeal Cancer - Molecular Biology

Pinto-Leite R, Carreira I, Melo J, et al.
Genomic characterization of three urinary bladder cancer cell lines: understanding genomic types of urinary bladder cancer.
Tumour Biol. 2014; 35(5):4599-617 [PubMed] Related Publications
Several genomic regions are frequently altered and associated with the type, stage and progression of urinary bladder cancer (UBC). We present the characterization of 5637, T24 and HT1376 UBC cell lines by karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis. Some cytogenetic anomalies present in UBC were found in the three cell lines, such as chromosome 20 aneuploidy and the loss of 9p21. Some gene loci losses (e.g. CDKN2A) and gains (e.g. HRAS, BCL2L1 and PTPN1) were coincident across all cell lines. Although some significant heterogeneity and complexity were detected between them, their genomic profiles exhibited a similar pattern to UBC. We suggest that 5637 and HT1376 represent the E2F3/RB1 pathway due to amplification of 6p22.3, concomitant with loss of one copy of RB1 and mutation of the remaining copy. The HT1376 presented a 10q deletion involving PTEN region and no alteration of PIK3CA region which, in combination with the inactivation of TP53, bears more invasive and metastatic properties than 5637. The T24 belongs to the alternative pathway of FGFR3/CCND1 by presenting mutated HRAS and over-represented CCND1. These cell lines cover the more frequent subtypes of UBC and are reliable models that can be used, as a group, in preclinical studies.

Related: Apoptosis CGH FISH Bladder Cancer Bladder Cancer - Molecular Biology

Byeon SJ, Cho HJ, Baek HW, et al.
Rhabdoid glioblastoma is distinguishable from classical glioblastoma by cytogenetics and molecular genetics.
Hum Pathol. 2014; 45(3):611-20 [PubMed] Related Publications
The clinicopathologic and molecular genetic features of 5 cases of rhabdoid glioblastoma, an extremely rare variant of glioblastoma that tends to affect patients at a young age, were investigated by immunohistochemical analysis and focused molecular genetic studies including array-based comparative genomic hybridization. All 5 cases had supratentorial tumors that immunohistochemical analysis revealed to be robustly positive for epithelial membrane antigen, vimentin, p53, and PDGFRα (platelet-derived growth factor receptor, alpha polypeptide) but only focally positive for glial fibrillary acidic protein. Although complete retention of SMARCB1 (INI1) was observed in all 5 cases, epidermal growth factor receptor (EGFR) amplification, PTEN (phosphatase and tensin homolog) loss, homozygous deletion of cyclin-dependent kinase inhibitor 2A, 1p/19q codeletion, and isocitrate dehydrogenase 1 R132/IDH2 R172 mutation were not observed in any case, although a high level of EGFR polysomy was detected in 1 recurrent tumor. Although c-MET (MET protein) expression was focal but robustly positive in 3 cases, met proto-oncogene (MET) fluorescence in situ hybridization revealed low polysomy but not MET amplification. MGMT (O-6-methylguanine-DNA methyl-40 transferase) methylation-specific polymerase chain reaction revealed MGMT methylation in only 1 case. Furthermore, array-based comparative genomic hybridization revealed gain of chromosome 7 and loss of 1p, 6, 8p, 11, 13q, and 18q but no deletion of chromosome 22. In contrast to the classical subtype of primary glioblastoma, the cases studied here were characterized by the absence of EGFR amplification, PTEN loss, and 9p homozygous deletion and overexpression of p53, PDGFRα, and c-MET, suggesting that they can be classified as the proneural or mesenchymal subtype of glioblastoma and benefit from intensive therapy that includes temozolomide.

Related: Cancer Cytogenetics EGFR

Kuhn E, Ayhan A, Bahadirli-Talbott A, et al.
Molecular characterization of undifferentiated carcinoma associated with endometrioid carcinoma.
Am J Surg Pathol. 2014; 38(5):660-5 [PubMed] Related Publications
Uterine and ovarian undifferentiated carcinomas (UCs) are often associated with low-grade endometrioid carcinomas (EMCs) and are characterized by a solid growth pattern and a lack of appreciable features of differentiation. As compared with pure EMC, UC is highly malignant, and the molecular pathogenesis that leads to disease aggressiveness remains largely unknown. This study interrogates the molecular pathogenesis of UCs by comparing the molecular alterations between the UC and the EMC components. A total of 20 UCs were studied, 12 of which contained both UC and EMC components. Mutation analysis was performed for the genes commonly mutated in EMC, and immunohistochemistry was used to determine the expression pattern of β-catenin and PTEN. Sequencing analysis revealed that UCs harbored somatic mutations in PIK3CA (50%), CTNNB1 (30%), TP53 (30%), FBXW7 (20%), and PPP2R1A (20%). All somatic mutations detected in EMCs were also present in concurrent UCs. Moreover, additional somatic mutations were detected in the UC component in 5 (42%) cases with concurrent EMC and UC. Concordance of immunostaining pattern for β-catenin and PTEN was recorded in all 12 matched EMCs and UCs, except 4 cases in which nuclear accumulation of β-catenin staining was detected in one of the components but not in the other. Our findings support a clonal relationship between EMCs and their associated UCs. Additional molecular genetics alteration, including mutations of CTNNB1, PPP2R1A, and TP53, may contribute to tumor progression from EMC to UC.

Related: Ovarian Cancer

Wu H, Wang K, Liu W, Hao Q
PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression.
Biochem Biophys Res Commun. 2014; 444(2):141-6 [PubMed] Related Publications
Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer.

Related: Apoptosis Cisplatin Ovarian Cancer

Thunnissen E, van der Oord K, den Bakker M
Prognostic and predictive biomarkers in lung cancer. A review.
Virchows Arch. 2014; 464(3):347-58 [PubMed] Related Publications
In lung cancer, clinically relevant prognostic information is provided by staging. Staging forms the basis for the treatment options and this is briefly summarized in the introduction. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase are biomarkers used for prediction of chemotherapy and prediction of targeted treatment. Other driver biomarkers in lung cancer (point mutations and rearrangements in specific genes including Her2, BRAF, NUT, MET, ROS1, DDR2, FGFR1, KRAS, and PTEN) might potentially provide additional information for clinical decision making. Owing to the low prevalence of mutations in predictive markers, patient numbers in studies are usually small, with the exception of EGFR. These mutations increase our understanding of the biology of lung cancer. Mutation analysis as a basis for treatment choice can have an impressive clinical impact with dramatic responses. However, as yet the impact of these approaches to overall survival is less striking.

Related: Lung Cancer EGFR


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