AKAP13

Gene Summary

Gene:AKAP13; A-kinase anchoring protein 13
Aliases: BRX, LBC, p47, HA-3, Ht31, c-lbc, PRKA13, AKAP-13, AKAP-Lbc, ARHGEF13, PROTO-LB, PROTO-LBC
Location:15q25.3
Summary:The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:A-kinase anchor protein 13
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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.

  • A Kinase Anchor Proteins
  • Neoplasm Invasiveness
  • Transfection
  • Neoplastic Cell Transformation
  • Biomarkers, Tumor
  • Neoplasm Metastasis
  • Drug Resistance
  • Oligonucleotide Array Sequence Analysis
  • Valine
  • Genetic Predisposition
  • Breast Cancer
  • alpha Catenin
  • Cancer Gene Expression Regulation
  • Sequence Homology
  • Cell Movement
  • Immunohistochemistry
  • Risk Factors
  • Amino Acid Sequence
  • Young Adult
  • Minor Histocompatibility Antigens
  • DNA Primers
  • GTP-Binding Proteins
  • Northern Blotting
  • Base Sequence
  • Signal Transducing Adaptor Proteins
  • Chromosome 15
  • Immunoenzyme Techniques
  • Cancer DNA
  • Gene Expression Profiling
  • Western Blotting
  • Proto-Oncogene Proteins
  • Molecular Sequence Data
  • Signal Transduction
  • rho GTP-Binding Proteins
  • Zinc Fingers
  • RTPCR
  • Neoplasm Recurrence, Local
  • Antineoplastic Agents
  • Quinolones
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AKAP13 (cancer-related)

Jajodia E, Raphael V, Shunyu NB, et al.
Brush Cytology and AgNOR in the Diagnosis of Oral Squamous Cell Carcinoma.
Acta Cytol. 2017; 61(1):62-70 [PubMed] Related Publications
OBJECTIVE: We aimed to evaluate the role of brush cytology in the screening of oral lesions with malignant suspicion and compare it with histopathology in north-eastern India.
STUDY DESIGN: Brush cytology samples taken from 48 patients were processed for conventional cytology (CC) and liquid-based cytology (LBC), and biopsy samples were also obtained. LBC samples were also stained to assess the argyrophilic nucleolar organizer region (AgNOR). The cytology was compared with histopathology, both individually and in combination with AgNOR. The smear quality was compared with histopathology for evaluating their diagnostic accuracy.
RESULTS: The sensitivity of diagnosing oral cavity squamous cell carcinoma by LBC and CC alone was 75 and 85%, respectively, which improved on combining with the AgNOR count, with a cutoff of 6.5. The presence of round cells on cytology was significantly associated with high-grade lesions. LBC provided clearer cytomorphology but compromised the background information in high-grade lesions.
CONCLUSION: Brush cytology is a minimally invasive tool for screening oral lesions with malignant suspicion. LBC and CC are complementary techniques for cytological screening and combining them with AgNOR can increase the diagnostic yield. With objective criteria for assessment, cytology can be an indispensable tool for screening oral lesions in a resource-limited set-up, especially in high-incidence regions.

White C, Bakhiet S, Bates M, et al.
Triage of LSIL/ASC-US with p16/Ki-67 dual staining and human papillomavirus testing: a 2-year prospective study.
Cytopathology. 2016; 27(4):269-76 [PubMed] Related Publications
OBJECTIVE: To investigate human papillomavirus (HPV) DNA testing and p16/Ki-67 staining for detecting cervical intraepithelial grade 2 or worse (CIN2+) and CIN3 in women referred to colposcopy with minor abnormal cervical cytology low-grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of undermined significance (ASC-US). The clinical performance of both tests was evaluated as stand-alone tests and combined, for detection CIN2+ and CIN3 over 2 years.
METHODS: ThinPrep(®) liquid-based cytology (LBC) specimens were collected from 1349 women with repeat LSIL or ASC-US. HPV DNA was performed using Hybrid Capture. Where adequate material remained (n = 471), p16/Ki-67 overexpression was assessed. Clinical performance for detection of histologically diagnosed CIN2+ and CIN3 was calculated.
RESULTS: Approximately 62.2% of the population were positive for HPV DNA, and 30.4% were positive for p16/Ki-67. p16/Ki-67 showed no significant difference in positivity between LSIL and ASC-US referrals (34.3% versus 28.6%; P = 0.189). Women under 30 years had a higher rate of p16/Ki-67 compared to those over 30 years (36.0% versus 26.6%; P = 0.029). Overall HPV DNA testing produced a high sensitivity for detection of CIN3 of 95.8% compared to 79.2% for p16/Ki-67. In contrast, p16/Ki-67 expression offered a higher specificity, 75.2% versus 40.4% for detection of CIN3. Combining p16/Ki-67 with HPV DNA improved the accuracy in distinguishing between CIN3 and CONCLUSION: The addition of p16/Ki-67 to HPV DNA testing leads to a more accurate stratification of CIN in women presenting with minor cytological abnormalities.

Phang BH, Othman R, Bougeard G, et al.
Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis.
Proc Natl Acad Sci U S A. 2015; 112(46):E6349-58 [PubMed] Free Access to Full Article Related Publications
Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53's apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival.

Xu L, Lu Y, Lai J, et al.
Characteristics of the TCR Vβ repertoire in imatinib-resistant chronic myeloid leukemia patients with ABL mutations.
Sci China Life Sci. 2015; 58(12):1276-81 [PubMed] Related Publications
Diversity in the T cell receptor (TCR) repertoire provides a miniature defense ability for the T cell immune system that may be related to tumor initiation and progression. Understanding the T cell immune status of leukemia patients is critical for establishing specific immunotherapies. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vβ T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vβ repertoire in 4 cases with imatinib-resistant CML in blast crisis (BC-CML) with abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase domain mutations (KDMs). Examination of TCR V expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) and GeneScan analysis. Significantly skewed TCR Vβ repertoires were observed in BC-CML patients with different KDMs, and 4 to 8 oligoclonally expanded TCR Vβ subfamilies could be identified in each sample. Intriguingly, a relatively highly expanded Vβ9 clone with the same length as complementarity- determining region 3 (CDR3) (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the only CML patient in myeloid blast crisis (MBC-CML). In conclusion, restricted TCR Vβ repertoire expression and decreased clone complexity was a general phenomenon observed in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency of these patients. In addition, clonally expanded Vβ9 T cell clones may indicate a specific immune response to leukemia-associated antigens in LBC-CML patients.

Lee IC, Chuang CC, Wu YC
Niche Mimicking for Selection and Enrichment of Liver Cancer Stem Cells by Hyaluronic Acid-Based Multilayer Films.
ACS Appl Mater Interfaces. 2015; 7(40):22188-95 [PubMed] Related Publications
Cancer stem cells (CSCs) represent a subpopulation of tumor cells that exhibit capacities for self-renewal, tumor initiation, disease relapse or metastasis, and resistance to chemotherapy and radiotherapy. However, the major obstacle associated with the use of CSCs is the difficulty in their isolation and enrichment. According to recent studies, CSCs share similar properties with normal stem cells, and it has been observed that hyaluronan (HA) plays a key factor in CSCs niches and that HA-mediated CD44 interaction promotes tumor progression. Therefore, HA-based multilayer films were used to fabricate sequential surface properties variation and to mimic CSC niches. A quartz crystal microbalance was used to investigate the layer-by-layer adsorption of PAH/HA multilayer films. Colony formation was observed on a series of poly(allylamine hydrochloride) PAH/HA multilayer films, and cytotoxicity and cell viability were evaluated by MTT, LDH and live/dead assay. It was observed that the cells isolated from (PAH/HA)3 displayed the best colony formation ability and that the expression of CD133/CD44 double positive cells was up-regulated to approximately 70% after 7 days of culture. Furthermore, the cells isolated from (PAH/HA)3 displayed higher chemo-resistance than the control group. The stem-cell-related genes expression of selected cells from (PAH/HA)3 after 7 days of culture was significantly different from that of the control group. In conclusion, this study provides a label-free selection and enrichment system that could serve as a new strategy for the future development of CSC selection and drug evaluation in cancer therapy.

Bentin Toaldo C, Alexi X, Beelen K, et al.
Protein Kinase A-induced tamoxifen resistance is mediated by anchoring protein AKAP13.
BMC Cancer. 2015; 15:588 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Estrogen Receptor alpha (ERα)-positive breast cancer patients receive endocrine therapy, often in the form of tamoxifen. However, resistance to tamoxifen is frequently observed. A signalling cascade that leads to tamoxifen resistance is dictated by activation of the Protein Kinase A (PKA) pathway, which leads to phosphorylation of ERα on Serine 305 and receptor activation, following tamoxifen binding. Thus far, it remains elusive what protein complexes enable the PKA-ERα interaction resulting in ERα Serine 305 phosphorylation.
METHODS: We performed immunohistochemistry to detect ERαSerine 305 phosphorylation in a cohort of breast cancer patients who received tamoxifen treatment in the metastatic setting. From the same tumor specimens, Agilent 44 K gene expression analyses were performed and integrated with clinicopathological data and survival information. In vitro analyses were performed using MCF7 breast cancer cells, which included immunoprecipitations and Fluorescence Resonance Energy Transfer (FRET) analyses to illustrate ERα complex formation. siRNA mediated knockdown experiments were performed to assess effects on ERαSerine 305 phosphorylation status, ERα/PKA interactions and downstream responsive gene activity.
RESULTS: Stratifying breast tumors on ERα Serine 305 phosphorylation status resulted in the identification of a gene network centered upon AKAP13. AKAP13 mRNA expression levels correlate with poor outcome in patients who received tamoxifen treatment in the metastatic setting. In addition, AKAP13 mRNA levels correlate with ERαSerine 305 phosphorylation in breast tumor samples, suggesting a functional connection between these two events. In a luminal breast cancer cell line, AKAP13 was found to interact with ERα as well as with a regulatory subunit of PKA. Knocking down of AKAP13 prevented PKA-mediated Serine 305 phosphorylation of ERα and abrogated PKA-driven tamoxifen resistance, illustrating that AKAP13 is an essential protein in this process.
CONCLUSIONS: We show that the PKA-anchoring protein AKAP13 is essential for the phosphorylation of ERαS305, which leads to tamoxifen resistance both in cell lines and tamoxifen-treated breast cancer patients.

Ma K, Wu HY, Zhang B, et al.
Neurotoxicity effects of atrazine-induced SH-SY5Y human dopaminergic neuroblastoma cells via microglial activation.
Mol Biosyst. 2015; 11(11):2915-24 [PubMed] Related Publications
Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) is a broad-spectrum herbicide with a wide range of applications worldwide. However, ATR is neurotoxic; it reduces dopamine levels in the substantia nigra and corpus striatum in the midbrain, affects the absorption of synaptic vesicles and synaptic bodies, and interferes with dopamine storage and uptake in synaptic vesicles, leading to neurodegenerative disorders. Microglia are resident immunocompetent and phagocytic cells that regulate and participate in the microenvironment in the central nervous system. They demonstrate macrophage characteristics after activation by releasing inflammatory cytokines and neurotoxic substances to increase the inflammatory response, and are thus involved in neurodegeneration. The aim of this study was to investigate the neurotoxic effects of ATR-activated microglia-mediated neuronal damage in terms of human dopaminergic neuroblastoma SH-SY5Y cell death. ATR was administered to BV-2 microglial cells at 12.5, 25, and 50 μM for 1, 6, 12, 24 and 48 h, respectively. ATR increased activated-microglia-induced overexpression of reactive oxygen species, inducible nitric oxide synthase, nitric oxide, gp91(phox), p47(phox), and the inflammatory cytokines tumor necrosis factor α and interleukin-1β, thus reducing SH-SY5Y cell viability. These results suggest that activated microglia may play a critical role in inflammation-mediated dopaminergic neuronal death, and provide the basis for further studies on the mechanisms of ATR-induced dopaminergic system toxicity.

van der Post RS, Vogelaar IP, Manders P, et al.
Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1.
Gastroenterology. 2015; 149(4):897-906.e19 [PubMed] Related Publications
BACKGROUND & AIMS: Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50.
METHODS: We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations.
RESULTS: In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P = .014 for comparative survival analysis between patients with and without a CDH1 mutation).
CONCLUSIONS: All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.

Telford BJ, Chen A, Beetham H, et al.
Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin-Deficient Cells.
Mol Cancer Ther. 2015; 14(5):1213-23 [PubMed] Related Publications
The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib. Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC.

Curigliano G, Bagnardi V, Bertolini F, et al.
Antiangiogenic therapy in recurrent breast cancer with lymphangitic spread to the chest wall: A randomized phase II trial of bevacizumab with sequential or concurrent oral vinorelbine and capecitabine.
Breast. 2015; 24(3):263-71 [PubMed] Related Publications
OBJECTIVES: To assess efficacy of bevacizumab in combination with oral chemotherapy in patients with breast cancer with lymphangitic spread to the chest wall (LBC). To identify surrogate biomarkers of response to bevacizumab.
PATIENTS AND METHODS: We randomly assigned patients to receive bevacizumab plus either sequential or concurrent oral vinorelbine and capecitabine every 3 weeks. The primary endpoint was time to ultimate progression (TTP); the response rate and overall survival (OS) were secondary endpoints. We performed gene expression profiling on baseline tissue samples collected from triple negative LBC. We assessed circulating endothelial cells (CEC), circulating endothelial progenitors (CEP) and circulating pericyte progenitors (CPP).
RESULTS: A total of 66 patients were enrolled. There was no difference in TTP (median TTP 5.3 vs. 4.8 months, p = 0.21) and in OS (median OS 15.8 vs 11.9 months; p = 0.25) when comparing concurrent vs sequential treatment, respectively. Response rate was 25% vs 28% in the concurrent vs sequential arm (p = 1.00), respectively. A set of 16 genes predictive of response to bevacizumab was identified. The counts of CEPs and viable CECs below the median value were associated with an improved overall survival: 26.6 vs 9.5 months for CEPs and 22.6 vs 11.0 months for viable CECs, respectively (p = 0.02).
CONCLUSIONS: Oral chemotherapy and bevacizumab (BEVIX) is an active regimen in patients with LBC. We support the importance of using LBC as a biological model for investigating angiogenesis inhibitors. CECs and CEPs biomarkers have been identified as predictive markers of outcome and warrant further investigation.

Wright TC, Compagno J, Romano P, et al.
Amplification of the 3q chromosomal region as a specific marker in cervical cancer.
Am J Obstet Gynecol. 2015; 213(1):51.e1-8 [PubMed] Related Publications
OBJECTIVE: Chromosome 3q gain has been consistently observed in cervical intraepithelial neoplasia grades 2 and 3 (CIN 2,3) and squamous cell carcinomas of the cervix. There are a number of potential clinical uses of testing for 3q gain in liquid cytology specimens, including the identification of subsets of women with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cytology who are at greatest risk of having CIN 2,3 and would thus benefit most from immediate colposcopy. The objective of this study was to establish the sensitivity and specificity of 3q gain for discriminating between CIN 2,3 and normal.
STUDY DESIGN: Residual cytology specimens were collected from 199 women. Liquid-based cytology (LBC) was used for the selection of subjects, with women with high-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion who had colposcopy and adjudicated biopsy-confirmed CIN 2,3 forming the disease-positive group (n = 28) and women doubly negative for both cytology and high-risk human papillomavirus (hrHPV) testing forming the disease-negative group (n = 171). A single slide was prepared from each residual LBC specimen and analyzed for 3q gain by fluorescent in situ hybridization, using a probe specific for the 3q26 region and a control probe for the chromosome 7 centromere. Two approaches were compared for the determination of 3q gain. The first was based on the analysis of an entire cervical cytology slide for the presence of rare cells with a high copy number (>4 copies) for the 3q locus. The second approach was based on the analysis of 400 cells to determine the percentage with 3 or more copies of the 3q locus.
RESULTS: Using the approach based on the detection of rare cells with a high copy number (>4 copies) for the 3q locus, 26 of the specimens from women with CIN 2,3 and none of the 171 specimens from women who were both hrHPV and cytology negative was positive for 3q gain. This translates to a sensitivity of 92.9% (95% confidence interval [CI], 76.5-98.9%), a specificity of 100% (95% CI, 97.8-100%), a positive predictive value of 100% (95% CI, 86.7-100%), and a negative predictive value of 98.8% (95% CI, 95.9-99.8), for distinguishing CIN 2,3 from normal.
CONCLUSION: These data support the potential clinical use of 3q gain for the evaluation of women in a number of clinical situations, including women with atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion, and those who are hrHPV positive.

Visnovsky J, Kudela E, Farkasova A, et al.
Amplification of TERT and TERC genes in cervical intraepithelial neoplasia and cervical cancer.
Neuro Endocrinol Lett. 2014; 35(6):518-22 [PubMed] Related Publications
OBJECTIVES: Telomerase is activated in various stages of oncogenesis. For cervical cancer, telomerase is already active in precancerous lesions. In our study we focused on the analysis of the amplification patterns of telomerase genes TERT and TERC.
DESIGN AND SETTING: We included 39 patients in our study between January 2012 and April 2013. Each patient underwent a classical gynaecological examination and a colposcopy. During the colposcopic examination we collected material for a Pap smear, HPV DNA test (HC2) and LBC (LiquiPrep™), and performed punch biopsies for histopathological evaluation. Residual cytologic sample was hybridized with the FISH probe and telomerase genes were analysed.
RESULTS: The amplification of the TERT gene showed us a very similar amplification pattern as TERC and gradually corresponded with both histolopathological (p<0.001) and cytopathological findings (p<0.001). The specificity and sensitivity of TERC gene amplification for the detection of CIN2+ lesions (cut off value 2.3) was 88.2% and 95.5% respectively (PPV 91.3%, NPV 93.8%).
CONCLUSIONS: We identified increasing amplification pattern of telomerase genes in cervical lesions. According to our results telomerase genes could help in the future to determine the malignant potential of cervical lesions and could be tested together with cytology and HPV DNA in order to obtain the highest combined sensitivity and specificity for CIN2+ lesion detection.

Son C, Kang EJ, Roh MS
Strategic management of transthoracic needle aspirates for histological subtyping and EGFR testing in patients with peripheral lung cancer: An institutional experience.
Diagn Cytopathol. 2015; 43(7):532-8 [PubMed] Related Publications
BACKGROUND: Lung cancer therapy is personalized based on the histological subtype and molecular status. Totally, 70% of lung cancer patients present in advanced stages and are diagnosed on small biopsy or cytology specimens, hence an accurate but tissue-sparing approach is necessary. This study aimed to demonstrate efficient utilization of cell block (CB) on transthoracic needle aspiration (TTNA) for lung cancer subtyping, and to investigate the usefulness of needle washing after TTNA for assessing EGFR molecular status.
METHODS: Each TTNA specimen from the 79 peripheral lung masses was divided into three parts; liquid-based cytology (LBC), CB (with or without immunohistochemistry), and needle washing for analysis of EGFR mutation using peptide nucleic acid-mediated real-time PCR clamping.
RESULTS: Totally 79 specimens were diagnosed as malignancy, 75 (94.9%), benign, 3 (3.8%), and inadequate specimen, 1 (1.3%). The combination of LBC and CB (92.0%) showed a higher diagnostic yield for definitive subtyping of lung cancer than LBC alone (72.0%). Of the 75 malignant cases, 17 (22.7%) showed an EGFR mutation in needle washing specimens. EGFR mutational status was compared in all paired needle washing and scraped CBs with a 100% concordance.
CONCLUSIONS: We hereby proposed a strategy to maximize biological information retrieval from a limited TTNA specimen in patients with peripheral lung cancer. This algorithm indicated CB preparation for accurate histological subtyping and waste needle washing for molecular testing.

Wu CY, Hou LK, Ren SX, et al.
High feasibility of liquid-based cytological samples for detection of EGFR mutations in Chinese patients with NSCLC.
Asian Pac J Cancer Prev. 2014; 15(18):7885-9 [PubMed] Related Publications
BACKGROUND: Activating mutations of epidermal growth factor receptor (EGFR) could predict response to tyrosine kinase inhibitor (TKI) treatment in patients with non-small cell lung cancer (NSCLC). However, the detection of EGFR mutation is frequently challenging in clinical practice for the lack of tumor tissue. The aim of this study was to investigate the feasibility of performing EGFR mutation testing on various types of liquid-based cytology (LBC) samples.
MATERIALS AND METHODS: A total of 434 liquid-based cytology samples were collected from March 2010 and November 2013. Among them, 101 with diagnosis of lung adenocarcinoma had paired surgically resected specimens. The ADx Amplification Refractory Mutation System (ADx-ARMS) was used to determine EGFR mutation status both in LBC and resected samples.
RESULTS: All liquid-based cytology samples were adequate for EGFR mutation analysis. The mutation rate was 50.5% in the 434 NSCLC patients with LBC samples and the incidence rates of EGFR mutation were consistent among different specimens. We also detected EGFR positives in 52.5% (53/101) patients with paired histologic specimens. The concordance rate of EGFR mutation between LBC samples and paired histologic specimens was 92.1%.
CONCLUSIONS: Our results suggest that liquid-based cytology samples are highly reliable for EGFR mutation testing in patients with NSCLC.

Nishimura R, Kagawa A, Tamogami S, et al.
Correlation of HER2 gene status assessment by fluorescence in situ hybridization between histological sections and cytological specimens of breast cancer.
Breast Cancer. 2016; 23(2):211-5 [PubMed] Related Publications
BACKGROUND: While HER2 gene detection in cytological specimens using fluorescence in situ hybridization (FISH) has been reported, the appropriate criteria for such specimens remain controversial.
METHODS: Fine needle aspiration (FNA) samples collected from surgically resected breast cancer specimens were rinsed in a cytopreservative solution containing fixative. Then, slides of the FNA samples were prepared by liquid-based cytology (LBC) (ThinPrep system, Hologic) according to the manufacturer's instructions, and a PathVision HER2 DNA probe kit (Abbott) was used for FISH staining. The results were evaluated using an automated MetaCyte imaging system (MetaSystems, Altlussheim, Germany). HER2 gene amplification was scored using the HER2/chromosome enumeration probe 17 (CEP17) signal count ratio as follows: amplified, >2.2; equivocal, 1.8-2.2; and unamplified, <1.8. The cytology results were compared with the histology results from concordant cases.
RESULTS: Successful results were obtained in 98 of 100 cases, and results from the FNA specimens were in agreement with those from the histological sections in 97 of these 98 cases (accuracy rate, 99 %; kappa, 0.962).
CONCLUSIONS: FISH-based assessment of the HER2 gene status is consistent between histological sections and cytological specimens of breast cancer.

Cottu P, Bièche I, Assayag F, et al.
Acquired resistance to endocrine treatments is associated with tumor-specific molecular changes in patient-derived luminal breast cancer xenografts.
Clin Cancer Res. 2014; 20(16):4314-25 [PubMed] Related Publications
PURPOSE: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC.
EXPERIMENTAL DESIGN: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays.
RESULTS: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival.
CONCLUSIONS: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314-25. ©2014 AACR.

Rossi ED, Martini M, Straccia P, et al.
Thyroglossal duct cyst cancer most likely arises from a thyroid gland remnant.
Virchows Arch. 2014; 465(1):67-72 [PubMed] Related Publications
Thyroglossal duct cancer is a rare entity, occurring in 1.5 % of all thyroglossal duct cysts (TDC). A definitive consensus about its neoplastic origin has not been established as two contrasting theories exist, one proposing an origin in extra-thyroid remnants and the other a metastatic localization of a primary thyroid cancer. We compare morphological and molecular characteristics of both thyroglossal and thyroid carcinomas in a case series from our institute. We evaluated histology of 80 TDC. In 12 cases, prior cytological evaluation had been performed by liquid-based cytology (LBC). The BRAF gene was examined for mutations, and the histology of both thyroglossal duct and synchronous thyroid carcinoma was reevaluated. In 9 out of 80 (11 %) TDC cases, a papillary thyroid cancer (PTC) was diagnosed. In five out of nine (56 %) thyroglossal carcinomas, a synchronous thyroid cancer was diagnosed: 3 PTC and 2 follicular variant PTC (FVPC). In five thyroglossal carcinomas, mutated BRAF (V600E) was found, three in PTC and in thyroglossal as well as in the synchronous tumor in the thyroid. All the patients are in a disease-free status and still alive. Our results suggest that the majority of thyroglossal carcinomas most likely develop as a primary malignancy from a thyroid remnant. Neither the presence of V600E BRAF mutations nor that of a well-differentiated thyroid carcinoma changed the outcome or disease-free survival. We suggest that a diagnosis of thyroglossal carcinoma should be followed by a detailed evaluation of the thyroid gland. In the absence of clinical and radiological thyroid alterations, follow-up as for thyroid cancer is the correct management.

Watanabe Y, Maeda I, Oikawa R, et al.
Aberrant DNA methylation status of DNA repair genes in breast cancer treated with neoadjuvant chemotherapy.
Genes Cells. 2013; 18(12):1120-30 [PubMed] Related Publications
Dysregulation of homologous recombination (HR) DNA repair has been implicated in breast carcinogenesis and chemosensitivity. Here, we investigated the methylation status of sixteen HR genes and analyzed their association with tumor subtypes and responses to neoadjuvant chemotherapy. Core specimens were obtained before neoadjuvant chemotherapy from sixty cases of primary breast cancer of the following four subgroups: luminal breast cancer (LBC) with pathological complete response (pCR), LBC with stable disease, triple-negative breast cancer (TNBC) with pCR and TNBC with poor response. The aberrant DNA methylation status of the following HR related-genes was analyzed using bisulfite-pyrosequencing: BRCA1, BRCA2, BARD1, MDC1, RNF8, RNF168, UBC13, ABRA1, PALB2, RAD50, RAD51, RAD51C, MRE11, NBS1, CtIP and ATM. Among the genes analyzed, only the incidence of BRCA1 and RNF8 methylation was significantly higher in TNBC than that in LBC. Whereas the incidence of BRCA1 methylation was tended to be higher in pCR cases than in poor-response cases in TNBC, that of RNF8 was significantly lower in pCR cases than in poor-response cases. Our results indicate that the methylation status of HR genes was not generally associated with TNBC subtype or chemosensitivity although hypermethylation of BRCA1 is associated with TNBC subtype and may impact chemosensitivity.

Molinaro V, Pensotti V, Marabelli M, et al.
Complementary molecular approaches reveal heterogeneous CDH1 germline defects in Italian patients with hereditary diffuse gastric cancer (HDGC) syndrome.
Genes Chromosomes Cancer. 2014; 53(5):432-45 [PubMed] Related Publications
Germline inactivation of the E-cadherin gene (CDH1) is associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant syndrome predisposing to both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). We searched for CDH1 germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives. We used a series of molecular methods, including: DNA sequencing, multiplex ligation-dependent probe amplification, single-nucleotide primer extension, bisulfite sequencing, reverse-transcription PCR, and bioinformatics tools. We identified pathogenic mutations in 6 out of 32 probands (19%): one truncating and two missense mutations, one large deletion, one allelic expression imbalance and one splicing defect. Three out of six CDH1 constitutive alterations were novel. Our data support the need for a multimethod approach for CDH1 genetic testing, demonstrating that both DNA and RNA analyses are required to increase the detection rate of pathogenic mutations, thus reducing the number of patients without a clear molecular diagnosis. On the whole, our results indicate that not only DGC patients, but also subjects with personal or family history of LBC might benefit from CDH1 genetic testing. Moreover, our findings support the notion that prophylactic gastrectomy should be offered to asymptomatic CDH1 mutation carriers; indeed, while endoscopic analysis with histological examination of random gastric biopsies can miss cancer foci, gastrectomy performed in these subjects always revealed foci of cancer cells.

Jajoo S, Mukherjea D, Kaur T, et al.
Essential role of NADPH oxidase-dependent reactive oxygen species generation in regulating microRNA-21 expression and function in prostate cancer.
Antioxid Redox Signal. 2013; 19(16):1863-76 [PubMed] Free Access to Full Article Related Publications
AIMS: Oncogenic microRNAs (miRs) promote tumor growth and invasiveness. One of these, miR-21, contributes to carcinogenesis in prostate and other cancers. In the present study, we tested the hypothesis that NADPH oxidase-dependent reactive oxygen species (ROS) regulate the expression and function of miR-21 and its target proteins, maspin and programmed cell death 4 (PDCD4), in prostate cancer cells.
RESULTS: The highly aggressive androgen receptor negative PC-3M-MM2 prostate cancer cells demonstrated high expression of miR-21 and p47(phox) (an essential subunit of NADPH oxidase). Using loss-of-function strategy, we showed that transfection of PC-3M-MM2 cells with anti-miR-21- and p47(phox) siRNA (si-p47(phox)) led to reduced expression of miR-21 with concurrent increase in maspin and PDCD4, and decreased the invasiveness of the cells. Tail-vein injections of anti-miR-21- and si-p47(phox)-transfected PC-3M-MM2 cells in severe combined immunodeficient mice reduced lung metastases. Clinical samples from patients with advanced prostate cancer expressed high levels of miR-21 and p47(phox), and low expression of maspin and PDCD4. Finally, ROS activated Akt in these cells, the inhibition of which reduced miR-21 expression.
INNOVATION: The levels of NADPH oxidase-derived ROS are high in prostate cancer cells, which have been shown to be involved in their growth and migration. This study demonstrates that ROS produced by this pathway is essential for the expression and function of an onco-miR, miR-21, in androgen receptor-negative prostate cancer cells.
CONCLUSION: These data demonstrate that miR-21 is an important target of ROS, which contributes to the highly invasive and metastatic phenotype of prostate cancer cells.

Jensen HA, Styskal LE, Tasseff R, et al.
The Src-family kinase inhibitor PP2 rescues inducible differentiation events in emergent retinoic acid-resistant myeloblastic leukemia cells.
PLoS One. 2013; 8(3):e58621 [PubMed] Free Access to Full Article Related Publications
Retinoic acid is an embryonic morphogen and dietary factor that demonstrates chemotherapeutic efficacy in inducing maturation in leukemia cells. Using HL60 model human myeloid leukemia cells, where all-trans retinoic acid (RA) induces granulocytic differentiation, we developed two emergent RA-resistant HL60 cell lines which are characterized by loss of RA-inducible G1/G0 arrest, CD11b expression, inducible oxidative metabolism and p47(phox) expression. However, RA-treated RA-resistant HL60 continue to exhibit sustained MEK/ERK activation, and one of the two sequentially emergent resistant lines retains RA-inducible CD38 expression. Other signaling events that define the wild-type (WT) response are compromised, including c-Raf phosphorylation and increased expression of c-Cbl, Vav1, and the Src-family kinases (SFKs) Lyn and Fgr. As shown previously in WT HL60 cells, we found that the SFK inhibitor PP2 significantly increases G1/G0 cell cycle arrest, CD38 and CD11b expression, c-Raf phosphorylation and expression of the aforementioned regulators in RA-resistant HL60. The resistant cells were potentially incapable of developing inducible oxidative metabolism. These results motivate the concept that RA resistance can occur in steps, wherein growth arrest and other differentiation events may be recovered in both emergent lines. Investigating the mechanistic anomalies in resistant cell lines is of therapeutic significance and helps to mechanistically understand the response to retinoic acid's biological effects in WT HL60 cells.

Tan LH, Tan SY, Tang T, et al.
Relationship between atypical T- and B-cell size predicts survival in peripheral T-cell lymphomas with large B-cells.
Pathology. 2013; 45(1):28-37 [PubMed] Related Publications
BACKGROUND: Pathological prognostication for peripheral T-cell lymphomas (PTCLs) complicated by large B-cell (LBC) proliferations has not been previously devised.
METHODS: Forty-six cases of PTCL with LBCs were reviewed immunohistologically, by in situ hybridisation for Epstein-Barr virus encoded RNA and polymerase chain reaction analyses for T-cell receptor (TCR) clonality. Follow-up intervals ranged from 1 to 149 months (mean 40 months).
RESULTS: Cases with atypical T-cell size equal to or exceeding that of interspersed LBCs (ATEB+, n = 12, including an ALK negative anaplastic large cell lymphoma) had significantly inferior disease-specific survival compared to ATEB negative (ATEB-, n = 34) cases (p = 0.002 for all cases and p = 0.014 when restricted to TCR clonal cases, n = 30) [hazard ratio 11.2; 95% confidence interval (CI) 0.94-85.0, p = 0.019]. All recorded deaths amongst ATEB+ cases occurred in 26 months, while TCR polyclonal ATEB- cases (n = 9) had none; TCR clonal ATEB- cases (n = 22) had 62% 5-year survival (95% CI 33-91%, p = 0.001). There was no survival separation between angioimmunoblastic (n = 25) and unspecified (n = 20) subsets of PTCL (p = 0.957).
CONCLUSION: In PTCLs, cytological grading using harboured LBCs as internal yardsticks, as well as molecular genotypic measures of lymphoma cell burden, have prognostic value.

Rossi ED, Martini M, Capodimonti S, et al.
BRAF (V600E) mutation analysis on liquid-based cytology-processed aspiration biopsies predicts bilaterality and lymph node involvement in papillary thyroid microcarcinoma.
Cancer Cytopathol. 2013; 121(6):291-7 [PubMed] Related Publications
BACKGROUND: Activating mutations in the valine-to-glutamic acid substitution at position 600 of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF-1) gene are detected frequently in patients with papillary thyroid carcinoma (PTC). These mutations have been identified in approximately 29% to 69% of PTCs and in >80% of PTCs of the tall cell variant, whereas they have not been detected in benign lesions or in the majority of those (80%) with the follicular variant of PTC. The objective of the current study was to evaluate the role of liquid-based cytology (LBC) for the detection of BRAF mutations in the outcome of patients who have thyroid PTC measuring ≤ 1 cm and, hence, in guiding their clinical and surgical management.
METHODS: From October 2010 through June 2011, 230 consecutive cases were diagnosed as positive for malignancy on fine-needle aspiration cytology processed by LBC. Of these, 73 PTCs ≤ 1 cm underwent BRAF mutational analysis. The aspirated material was processed using an LBC technique. After DNA extraction of the residual material, BRAF mutation analysis was performed using a direct sequencing method.
RESULTS: Fifty of 73 patients (68.5%) underwent surgery, and 34 of those patients (68%) had tumors that expressed a BRAF mutation (31 PTCs, including 11 tall cell variants and 3 follicular-variant PTCs). A significant association between BRAF mutation and bilaterality of cancer was observed (odds ratio, 0.077; P = .0007). BRAF mutation was associated significantly with lymph node involvement (odds ratio, 19; P = .0007) but not with extracapsular infiltration (odds ratio, 0.298; P = .179).
CONCLUSIONS: The current results indicated that BRAF gene mutations can be identified successfully on LBC material and using other cytologic methods with high reproducibility, feasibility, and informative results. The presence of a BRAF mutation may preoperatively predict the behavior of microscopic PTC, suggesting a more aggressive surgical approach.

Carr HS, Morris CA, Menon S, et al.
Rac1 controls the subcellular localization of the Rho guanine nucleotide exchange factor Net1A to regulate focal adhesion formation and cell spreading.
Mol Cell Biol. 2013; 33(3):622-34 [PubMed] Free Access to Full Article Related Publications
RhoA is overexpressed in human cancer and contributes to aberrant cell motility and metastatic progression; however, regulatory mechanisms controlling RhoA activity in cancer are poorly understood. Neuroepithelial transforming gene 1 (Net1) is a RhoA guanine nucleotide exchange factor that is overexpressed in human cancer. It encodes two isoforms, Net1 and Net1A, which cycle between the nucleus and plasma membrane. Net1 proteins must leave the nucleus to activate RhoA, but mechanisms controlling the extranuclear localization of Net1 isoforms have not been described. Here, we show that Rac1 activation causes relocalization of Net1 isoforms outside the nucleus and stimulates Net1A catalytic activity. These effects do not require Net1A catalytic activity, its pleckstrin homology domain, or its regulatory C terminus. We also show that Rac1 activation protects Net1A from proteasome-mediated degradation. Replating cells on collagen stimulates endogenous Rac1 to relocalize Net1A, and inhibition of proteasome activity extends the duration and magnitude of Net1A relocalization. Importantly, we demonstrate that Net1A, but not Net1, is required for cell spreading on collagen, myosin light chain phosphorylation, and focal adhesion maturation. These data identify the first physiological mechanism controlling the extranuclear localization of Net1 isoforms. They also demonstrate a previously unrecognized role for Net1A in regulating cell adhesion.

Neumeister VM, Anagnostou V, Siddiqui S, et al.
Quantitative assessment of effect of preanalytic cold ischemic time on protein expression in breast cancer tissues.
J Natl Cancer Inst. 2012; 104(23):1815-24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Companion diagnostic tests can depend on accurate measurement of protein expression in tissues. Preanalytic variables, especially cold ischemic time (time from tissue removal to fixation in formalin) can affect the measurement and may cause false-negative results. We examined 23 proteins, including four commonly used breast cancer biomarker proteins, to quantify their sensitivity to cold ischemia in breast cancer tissues.
METHODS: A series of 93 breast cancer specimens with known time-to-fixation represented in a tissue microarray and a second series of 25 matched pairs of core needle biopsies and breast cancer resections were used to evaluate changes in antigenicity as a function of cold ischemic time. Estrogen receptor (ER), progesterone receptor (PgR), HER2 or Ki67, and 19 other antigens were tested. Each antigen was measured using the AQUA method of quantitative immunofluorescence on at least one series. All statistical tests were two-sided.
RESULTS: We found no evidence for loss of antigenicity with time-to-fixation for ER, PgR, HER2, or Ki67 in a 4-hour time window. However, with a bootstrapping analysis, we observed a trend toward loss for ER and PgR, a statistically significant loss of antigenicity for phosphorylated tyrosine (P = .0048), and trends toward loss for other proteins. There was evidence of increased antigenicity in acetylated lysine, AKAP13 (P = .009), and HIF1A (P = .046), which are proteins known to be expressed in conditions of hypoxia. The loss of antigenicity for phosphorylated tyrosine and increase in expression of AKAP13, and HIF1A were confirmed in the biopsy/resection series.
CONCLUSIONS: Key breast cancer biomarkers show no evidence of loss of antigenicity, although this dataset assesses the relatively short time beyond the 1-hour limit in recent guidelines. Other proteins show changes in antigenicity in both directions. Future studies that extend the time range and normalize for heterogeneity will provide more comprehensive information on preanalytic variation due to cold ischemic time.

Di Lorito A, Rosini S, Falò E, et al.
Molecular alterations in endometrial archived liquid-based cytology.
Diagn Cytopathol. 2013; 41(6):492-6 [PubMed] Related Publications
Endometrial cancer is one of the most common gynecological malignancy worldwide and its prevalence is increasing. The introduction of liquid-based cytology (LBC) and endoflower dispositive in routine practice gives the possibility to examine endometrial cells by cytological diagnosis and may also release the opportunity to study molecular alterations, in endometrioid type cancer in which carcinogenesis is well known. We gathered 72 cases of endometrial LBC samples and corresponding formalin-fixed paraffin-embedded (FFPE) blocks, collected from 2004 to 2010. DNA was isolated from both samples using standard protocols. DNA quality and quantity were assessed using Nanodrop and BIOMED2 multiplex PCR. Mutations in exon 5 of PTEN and exon 20 of PI3K were studied using Sanger sequencing. DNA with good quality and amount was isolated from 67/72 FFPE cases. In these samples, two cases were found to harbor mutations in exon 5 of PTEN. No PI3K mutations were identified. LBC samples were then assessed to verify the concordance with the FFPE DNA results. The results obtained were concordant, that is the wild type cases in FFPE were also wild type in LBC and vice versa for the mutated case. Unfortunately, the second case of mutation in PTEN could not be confirmed in LBC due to low amount of DNA obtained. Detection of molecular alterations in LBC will open a new era for the detection in asymptomatic women of precursor lesions that could evolve into cancer and for endometrial cancer diagnosis and screening in selected high-risk women.

Cao C, Chen Y, Masood R, et al.
α-Catulin marks the invasion front of squamous cell carcinoma and is important for tumor cell metastasis.
Mol Cancer Res. 2012; 10(7):892-903 [PubMed] Free Access to Full Article Related Publications
Squamous cell carcinomas (SCC) comprise the most common types of human epithelial cancers. One subtype, head and neck squamous cell carcinoma (HNSCC), is a particularly aggressive cancer with poor prognosis due to late diagnosis and lymph node metastasis. Of all the processes involved in carcinogenesis, local invasion and distant metastasis are clinically the most relevant, but are the least well understood on a molecular level. Here, we find that in vivo, the α-catenin homologue-α-catulin, a protein originally reported to interact with Lbc Rho guanine nucleotide exchange factor, is highly expressed at the tumor invasion front and in the metastatic streams of cells in both malignant hHNSCCs and a mouse model of oral SCC. Knockdown of α-catulin in hHNSCC cell lines dramatically decrease the migratory and invasive potential of those cells in vitro and metastatic potential in xenotransplants in vivo. Analysis of tumors deficient in α-catulin showed that the tumor cells are unable to invade the surrounding stroma. Accordingly, transcriptional profiling of those tumors revealed that α-catulin ablation is accompanied by changes in genes involved in cell migration and invasion. Interestingly enough, in vitro experiments show that an upregulation of α-catulin expression correlates with the transition of tumor cells from an epithelial to a mesenchymal morphology, as well as an upregulation of epithelial-to-mesenchymal transition (EMT) markers vimentin and snail. Overall, these results strongly indicate that α-catulin contributes to the invasive behavior of metastatic cells and may be used as a prognostic marker and future therapeutic target for patients with cancer.

González F, Nair KS, Daniels JK, et al.
Hyperandrogenism sensitizes leukocytes to hyperglycemia to promote oxidative stress in lean reproductive-age women.
J Clin Endocrinol Metab. 2012; 97(8):2836-43 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Hyperandrogenism and oxidative stress are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate oxidative stress.
OBJECTIVE: The purpose of this study was to determine the effect of oral androgen administration on fasting and glucose-stimulated leukocytic reactive oxygen species (ROS) generation, reduced nicotinamide adenine dinucleotide phosphate oxidase p47(phox) subunit gene expression, and plasma thiobarbituric acid-reactive substances (TBARS) in lean healthy reproductive-age women.
PARTICIPANTS, DESIGN, AND SETTING: Sixteen lean healthy ovulatory reproductive-age women were treated with 130 mg dehydroepiandrosterone (DHEA) or placebo (n = 8 each) for 5 d in this randomized, controlled, double-blind study that was performed at an an academic medical center.
MAIN OUTCOME MEASURES: Leukocytic ROS generation, p47(phox) gene expression, and plasma TBARS were quantified in the fasting state and 2 h after glucose ingestion, before and after treatment.
RESULTS: Before treatment, subjects receiving DHEA or placebo exhibited no differences in androgens or any prooxidant markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-sulfate, increased the percent change in glucose-challenged p47(phox) RNA content, and increased the percent change in fasting and glucose-challenged ROS generation from mononuclear cells and polymorphonuclear cells, p47(phox) protein content, and plasma TBARS.
CONCLUSION: Elevation of circulating androgens comparable to what is present in PCOS increases leukocytic ROS generation, p47(phox) gene expression, and plasma TBARS to promote oxidative stress in lean healthy reproductive-age women. Thus, hyperandrogenemia activates and sensitizes leukocytes to glucose in this population.

Palka Bayard de Volo C, Alfonsi M, Gatta V, et al.
16q22.1 microdeletion detected by array-CGH in a family with mental retardation and lobular breast cancer.
Gene. 2012; 498(2):328-31 [PubMed] Related Publications
We describe the case of a boy with psychomotor delay and dysmorphic features, with a germline 16q22.1 microdeletion identified by array-CGH. The deletion spans 0.24Mb and encompasses three genes (ZFP90, CDH3 and CDH1). The deletion has been demonstrated to be inherited from his mother who was affected by lobular breast cancer (LBC) without any other apparently phenotypic features. We suppose that the microdeletion, in particular ZFP90 which is cerebrally expressed, is causative for the boy's phenotype. Mental retardation in the affected boy can recognize several mechanisms such as variable expressivity, non-penetrance, multifactorial/polygenic inheritance, recessive inheritance, a second rearrangement event and epigenetics. Furthermore, we suggest that the deletion of the CDH1, a tumor suppressor gene, involved in hereditary diffuse gastric cancer (HDGC) and LBC predisposed the mother to the carcinoma.

Fehér LZ, Pocsay G, Krenács L, et al.
Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.
Pathol Oncol Res. 2012; 18(2):449-58 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) is the most common well-differentiated thyroid cancer. Although the great majority of the cases exhibit an indolent clinical course, some of them develop local invasion with distant metastasis, and a few cases transform into undifferentiated/anaplastic thyroid carcinoma with a rapidly lethal course. To identify gene copy number alterations predictive of metastatic potential or aggressive transformation, array-based comparative genomic hybridization (CGH-array) was performed in 43 PTC cases. Formalin-fixed and paraffin-embedded samples from primary tumours of 16 cases without metastasis, 14 cases with only regional lymph node metastasis, and 13 cases with distant metastasis, recurrence or extrathyroid extension were analysed. The CGH-array and confirmatory quantitative real-time PCR results identified the deletion of the EIF4EBP3 and TRAK2 gene loci, while amplification of thymosin beta 10 (TB10) and Tre-2 oncogene regions were observed as general markers for PTC. Although there have been several studies implicating TB10 as a specific marker based on gene expression data, our study is the first to report on genomic amplification. Although no significant difference could be detected between the good and bad prognosis cases in the A-kinase anchor protein 13 (AKAP13) gene region, it was discriminative markers for metastasis. Amplification in the AKAP13 region was demonstrated in 42.9% and 15.4% of the cases with local or with distant metastasis, respectively, while no amplification was detected in non-metastatic cases. AKAP13 and TB10 regions may represent potential new genomic markers for PTC and cancer progression.

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