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FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2
Zuo, Tao
Liu, Runhua
Zhang, Huiming
Chang, Xing
Liu, Yan
Wang, Lizhong
Zheng, Pan
Liu, Yang
The Journal of Clinical Investigation
S-phase kinase-associated protein 2 (SKP2) is a component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex. Overexpression of SKP2 results in cell cycle dysregulation and carcinogenesis; however, the genetic lesions that cause this upregulation are poorly understood. We recently demonstrated that forkhead box P3 (FOXP3) is an X-linked breast cancer suppressor and an important repressor of the oncogene ERBB2/HER2. Since FOXP3 suppresses tumor growth regardless of whether the tumors overexpress ERBB2/HER2, additional FOXP3 targets may be involved in its tumor suppressor activity. Here, we show that mammary carcinomas from mice heterozygous for a Foxp3 mutation exhibited increased Skp2 expression. Ectopic expression of FOXP3 in mouse mammary cancer cells repressed SKP2 expression with a corresponding increase in p27 and polyploidy. Conversely, siRNA silencing of the FOXP3 gene in human mammary epithelial cells increased SKP2 expression. We also show that Foxp3 directly interacted with and repressed the Skp2 promoter. Moreover, the analysis of over 200 primary breast cancer samples revealed an inverse correlation between FOXP3 and SKP2 levels. Finally, we demonstrated that downregulation of SKP2 was critical for FOXP3-mediated growth inhibition in breast cancer cells that do not overexpress ERBB2/HER2. Our data provide genetic, biochemical, and functional evidence that FOXP3 is a novel transcriptional repressor for the oncogene SKP2.
Related Articles
ZNF217, a candidate breast cancer oncogene amplified at 20q13, regulates expression of the ErbB3 receptor tyrosine kinase in breast cancer cells
Krig, Sheryl R.
Miller, Jamie K.
Frietze, Seth
Beckett, Laurel A.
Neve, Richard M.
Farnham, Peggy J.
Yaswen, Paul I.
Sweeney, Colleen A.
Understanding the mechanisms underlying ErbB3 over-expression in breast cancer will facilitate the rational design of therapies to disrupt ErbB2-ErbB3 oncogenic function. While ErbB3 over-expression is frequently observed in breast cancer, the factors mediating its aberrant expression are poorly understood. In particular, the ErbB3 gene is not significantly amplified, raising the question as to how ErbB3 over-expression is achieved. In this study we demonstrate that the ZNF217 transcription factor, amplified at 20q13 in ~20% of breast tumors, regulates ErbB3 expression. Analysis of a panel of human breast cancer cell lines (n = 50) and primary human breast tumors (n=15) demonstrated a strong positive correlation between ZNF217 and ErbB3 expression. Ectopic expression of ZNF217 in human mammary epithelial cells induced ErbB3 expression while ZNF217 silencing in breast cancer cells resulted in decreased ErbB3 expression. While ZNF217 has previously been linked with transcriptional repression due to its close association with CtBP1/2 repressor complexes, our results demonstrate that ZNF217 also activates gene expression. We demonstrate that ZNF217 recruitment to the ErbB3 promoter is CtBP1/2-independent and that ZNF217 and CtBP1/2 play opposite roles in regulating ErbB3 expression. In addition, we identify ErbB3 as one of the mechanisms by which ZNF217 augments PI-3K/Akt signaling.
ZNF217; ErbB3; CtBP2; 20q13; breast cancer
Related Articles
ErbB3 is required for ductal morphogenesis in the mouse mammary gland
Jackson-Fisher, Amy J
Bellinger, Gary
Breindel, Jerrica L
Tavassoli, Fatteneh A
Booth, Carmen J
Duong, James K
Stern, David F
Breast Cancer Research : BCR
The receptor ErbB3/HER3 is often over-expressed in human breast cancers, frequently in conjunction with over-expression of the proto-oncogene ERBB2/HER2/NEU. Although the prognostic/predictive value of ErbB3 expression in breast cancer is unclear, ErbB3 is known to contribute to therapeutic resistance. Understanding ErbB3 functions in the normal mammary gland will help to explain its role in cancer etiology and as a modulator of signaling responses to the mammary oncogene ERBB2.
To investigate the roles of ErbB3 in mouse mammary gland development, we transplanted mammary buds from ErbB3-/- embryos into the cleared mammary fat pads of wild-type immunocompromised mice. Effects on ductal outgrowth were analyzed at 4 weeks, 7 weeks and 20 weeks after transplantation for total ductal outgrowth, branch density, and number and area of terminal end buds. Sections of glands containing terminal end buds were analyzed for number and epithelial area of terminal end buds. Terminal end buds were also analyzed for presence of mitotic figures, apoptotic figures, BrdU incorporation, and expression of E-cadherin, P-cadherin, α-smooth muscle actin, and cleaved caspase-3.
The mammary ductal trees developed from ErbB3-/- buds only partly filled the mammary fat pad. In contrast to similar experiments with ErbB2-/- mammary buds, this phenotype was maintained through adulthood, pregnancy, and parturition. In addition, and in contrast to similar work with ErbB4-/- mammary buds, lobuloalveolar development of ErbB3-/- transplanted glands was normal. The ErbB3-/- mammary outgrowth defect was associated with a decrease in the size of the terminal end buds, and with increases in branch density, in the number of terminal end buds, and in the number of luminal spaces. Proliferation rates were not affected by the lack of ErbB3, but there was an increase in apoptosis in ErbB3-/- terminal end buds.
Endogenous ErbB3 regulates morphogenesis of mammary epithelium.
Related Articles
Inhibition of eIF2α dephosphorylation inhibits ErbB2-induced deregulation of mammary acinar morphogenesis
Sequeira, Sharon J
Wen, Huei Chi
Avivar-Valderas, Alvaro
Farias, Eduardo F
Aguirre-Ghiso, Julio A
BMC Cell Biology
The ErbB2/Her2/Neu receptor tyrosine kinase is amplified in ~30% of human breast cancers. Phosphorylation of the translation initiation factor, eIF2α inhibits global protein synthesis and activates a stress signaling and growth suppressive program. We have shown that forced phosphorylation of eIF2α can suppress head and neck, colorectal carcinoma and multiple myeloma tumor growth and/or survival. Here we explore whether ErbB2 modulates eIF2α phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis.
We tested whether ErbB2 signaling influenced eIF2α signaling and whether enhanced phosphorylation of the latter affected ErbB2-deregulated mammary acinar development. We obtained stable MCF10A cells overexpressing wild-type (Wt) Neu/ErbB2 or a constitutively active (CA) variant via retroviral delivery or mammary tumor cells from MMTV-Neu tumors. Western blotting, RT-PCR and confocal microscopy were used to analyze the effects of ErbB2 activation on eIF2α signaling and the effect of the GADD34-PP1C inhibitor salubrinal. Wt- and MMTV-Neu cells formed aberrant acini structures resembling DCIS, while CA-ErbB2 overexpression induced invasive lesions. In these structures we found that CA-ErbB2 but not the Wt variant significantly down-regulated the pro-apoptotic gene CHOP. This occurred without apparent modulation of basal phosphorylation of PERK and eIF2α or induction of its downstream target ATF4. However, inhibition of eIF2α dephosphorylation with salubrinal was sufficient to inhibit Wt- and CA-ErbB2- as well as MMTV-Neu-induced deregulation of acinar growth. This was linked to enhanced CHOP expression, inhibition of proliferation, induction of apoptosis and luminal clearing in Wt-ErbB2 and to inhibition of cyclin D1 levels and subsequent proliferation in CA-ErbB2 cells.
Depending on the strength of ErbB2 signaling there is a differential regulation of CHOP and eIF2α phosphorylation. ErbB2 uncouples in basal conditions eIF2α phosphorylation from CHOP induction. However, this signal was restored by salubrinal treatment in Wt-ErbB2 expressing MCF10A cells as these DCIS-like structures underwent luminal clearing. In CA-ErbB2 structures apoptosis is not induced by salubrinal and instead a state of quiescence with reduced proliferation was achieved. Treatments that stabilize P-eIF2α levels may be effective in treating ErbB2 positive cancers without severely disrupting normal tissue function and structure.
Related Articles
Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family
Arkhipov, Anton
Shan, Yibing
Kim, Eric T
Dror, Ron O
Shaw, David E
The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodimerization, however, remains poorly understood. The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric. Here, we report results from long-timescale molecular dynamics simulations indicating that a single ligand is necessary and sufficient to stabilize the ectodomain interface of Her2 heterodimers, which assume an asymmetric conformation similar to that of dEGFR dimers. This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human.
DOI: http://dx.doi.org/10.7554/eLife.00708.001
eLife digest
ErbB proteins are found in most multi-cellular organisms, and are involved in the regulation of a number of important cellular processes, including proliferation, migration, and differentiation. Humans have four ErbB proteins, which span the plasma membrane of cells. These proteins respond to interactions with molecules outside the cell—such as growth factors and hormones—by sending signals along the appropriate signaling pathway within the cell.
ErbB proteins have three portions: an ectodomain that extends outside the cell; a single helix that spans the membrane; and a cytoplasmic domain inside the cell. When a signaling ligand molecule outside the cell binds to the ectodomain of an ErbB protein, this protein must then combine with another ErbB protein to form a dimer before a signal can be sent within the cell. These dimers can include two copies of the same ErbB protein or two different ErbB proteins. However, one of the ErbB proteins—Her2—works in a different way. It cannot bind ligands outside the cell, and it can only send a signal within the cell if it first forms a dimer with an ErbB protein of another type, which itself must be bound to an external ligand.
The four ErbB proteins diverged from a common ancestor relatively recently, yet they are now diverse enough to play key roles in a variety of complex signaling networks. In particular, the fact that Her2 cannot bind external ligands, and that it must form a dimer with a different ErbB protein before it can send a signal, has led to suggestions that the role of Her2 is to amplify the signals from other ErbB proteins. Since high levels of Her2 are associated with aggressive forms of breast and ovarian cancer, understanding how it is activated could improve our understanding of these cancers.
Arkhipov et al. have now used computer simulations to model how Her2 forms dimers with other ErbB proteins in human cells. They based these simulations on crystal structures of human ErbB proteins and dEGFR, a growth-factor receptor found in fruit flies that closely resembles the ErbB proteins found in humans. They found that the dimers were stable as long as one protein within the dimer was bound to a ligand. Removing this ligand, however, distorted the ectodomain of the host protein, creating a gap that weakened the dimer and prevented Her2 from sending a signal within the cell. Similar results were obtained with the fruit fly dEGFR proteins. These simulations suggest that ErbB proteins form dimers and send signals through a mechanism conserved in evolution. Research in this field might help ongoing efforts to develop new treatments for human tumors characterized by high levels of Her2 expression.
DOI: http://dx.doi.org/10.7554/eLife.00708.002
Her2/ErbB2 activation; extracellular domain conformation; dimerization interface; None
Related Articles
Modulation of ErbB2 Blockade in ErbB2-Positive Cancers: The Role of ErbB2 Mutations and PHLDA1
Li, Guangyuan
Wang, Xiaoqi
Hibshoosh, Hanina
Jin, Cheng
Halmos, Balazs
PLoS ONE
We set out to study the key effectors of resistance and sensitivity to ErbB2 tyrosine kinase inhibitors, such as lapatinib in ErbB2-positive breast and lung cancers. A cell-based in vitro site-directed mutagenesis lapatinib resistance model identified several mutations, including the gatekeeper ErbB2 mutation ErbB2-T798I, as mediating resistance. ErbB2-T798I engineered cell models indeed show resistance to lapatinib but remain sensitive to the irreversible EGFR/ErbB2 inhibitor, PD168393, suggestive of potential alternative treatment strategies to overcome resistance. Gene expression profiling studies identified a select group of downstream targets regulated by ErbB2 signaling and define PHLDA1 as an immediately downregulated gene upon oncogenic ErbB2 signaling inhibition. We find significant down-regulation of PHLDA1 in primary breast cancer and PHLDA1 is statistically significantly less expressed in ErbB2 negative compared with ErbB2 positive tumors consistent with its regulation by ErbB2. Lastly, PHLDA1 overexpression blocks AKT signaling, inhibits cell growth and enhances lapatinib sensitivity further supporting an important negative growth regulator function. Our findings suggest that PHLDA1 might have key inhibitory functions in ErbB2 driven lung and breast cancer cells and a better understanding of its functions might point at novel therapeutic options. In summary, our studies define novel ways of modulating sensitivity and resistance to ErbB2 inhibition in ErbB2-dependent cancers.
Related Articles
Activated Akt1 accelerates MMTV-c-ErbB2 mammary tumourigenesis in mice without activation of ErbB3
Young, Christian D
Nolte, Erica C
Lewis, Andrew
Serkova, Natalie J
Anderson, Steven M
Breast Cancer Research : BCR
ErbB2, a member of the epidermal growth factor receptor (EGFR) family, is overexpressed in 20% to 30% of human breast cancer cases and forms oncogenic signalling complexes when dimerised to ErbB3 or other EGFR family members.
We crossed mouse mammary tumour virus (MMTV)-myr-Akt1 transgenic mice (which express constitutively active Akt1 in the mammary gland) with MMTV-c-ErbB2 transgenic mice to evaluate the role of Akt1 activation in ErbB2-induced mammary carcinoma using immunoblot analysis, magnetic resonance spectroscopy and histological analyses.
Bitransgenic MMTV-c-ErbB2, MMTV-myr-Akt1 mice develop mammary tumours twice as fast as MMTV-c-ErbB2 mice. The bitransgenic tumours were less organised, had more mitotic figures and fewer apoptotic cells. However, many bitransgenic tumours displayed areas of extensive necrosis compared with tumours from MMTV-c-ErbB2 mice. The two tumour types demonstrate dramatically different expression and activation of EGFR family members, as well as different metabolic profiles. c-ErbB2 tumours demonstrate overexpression of EGFR, ErbB2, ErbB3 and ErbB4, and activation/phosphorylation of both ErbB2 and ErbB3, underscoring the importance of the entire EGFR family in ErbB2-induced tumourigenesis. Tumours from bitransgenic mice overexpress the myr-Akt1 and ErbB2 transgenes, but there was dramatically less overexpression and phosphorylation of ErbB3, diminished phosphorylation of ErbB2, decreased level of EGFR protein and undetectable ErbB4 protein. There was also an observable attenuation in a subset of tyrosine-phosphorylated secondary signalling molecules in the bitransgenic tumours compared with c-ErbB2 tumours, but Erk was activated/phosphorylated in both tumour types. Finally, the bitransgenic tumours were metabolically more active as indicated by increased glucose transporter 1 (GLUT1) expression, elevated lactate production and decreased intracellular glucose (suggesting increased glycolysis).
Expression of activated Akt1 in MMTV-c-ErbB2 mice accelerates tumourigenesis with a reduced requirement for signalling through the EGFR family, as well as a reduced requirement for a subset of downstream signaling molecules with a metabolic shift in the tumours from bitransgenic mice. The reduction in signalling downstream of ErbB2 when Akt is activated suggest a possible mechanism by which tumour cells can become resistant to ErbB2-targeted therapies, necessitating therapies that target oncogenic signalling events downstream of ErbB2.
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HER3 Is Required for HER2-Induced Preneoplastic Changes to the Breast Epithelium and Tumor Formation
Vaught, David B.
Stanford, Jamie C.
Young, Christian
Hicks, Donna J.
Wheeler, Frank
Rinehart, Cammie
Sánchez, Violeta
Koland, John
Muller, William J.
Arteaga, Carlos L.
Cook, Rebecca S.
Cancer research
Increasing evidence suggests that HER2-amplified breast cancer cells use HER3/ErbB3 to drive therapeutic resistance to HER2 inhibitors. However, the role of ErbB3 in the earliest events of breast epithelial transformation remains unknown. Using mouse mammary specific models of Cre-mediated ErbB3 ablation, we show that ErbB3 loss prevents the progressive transformation of HER2-overexpressing mammary epithelium. Decreased proliferation and increased apoptosis were seen in MMTV-HER2 and MMTV-Neu mammary glands lacking ErbB3, thus inhibiting premalignant HER2-induced hyperplasia. Using a transgenic model in which HER2 and Cre are expressed from a single polycistronic transcript, we showed that palpable tumor penetrance decreased from 93.3% to 6.7% upon ErbB3 ablation. Penetrance of ductal carcinomas in situ was also decreased. In addition, loss of ErbB3 impaired Akt and p44/42 phosphorylation in preneoplastic HER2-overexpressing mammary glands and in tumors, decreased growth of preexisting HER2-overexpressing tumors, and improved tumor response to the HER2 tyrosine kinase inhibitor lapatinib. These events were rescued by reexpression of ErbB3, but were only partially rescued by ErbB36F, an ErbB3 mutant harboring six tyrosine-to-phenylalanine mutations that block its interaction with phosphatidyl inositol 3-kinase. Taken together, our findings suggest that ErbB3 promotes HER2-induced changes in the breast epithelium before, during, and after tumor formation. These results may have important translational implications for the treatment and prevention of HER2-amplified breast tumors through ErbB3 inhibition.
Related Articles
Expression Profiling during Mammary Epithelial Cell Three-Dimensional Morphogenesis Identifies PTPRO as a Novel Regulator of Morphogenesis and ErbB2-Mediated Transformation
Yu, Min
Lin, Guang
Arshadi, Niloofar
Kalatskaya, Irina
Xue, Bin
Haider, Syed
Nguyen, Francis
Boutros, Paul C.
Elson, Ari
Muthuswamy, Lakshmi B.
Tonks, Nicholas K.
Muthuswamy, Senthil K.
Molecular and Cellular Biology
Identification of genes that are upregulated during mammary epithelial cell morphogenesis may reveal novel regulators of tumorigenesis. We have demonstrated that gene expression programs in mammary epithelial cells grown in monolayer cultures differ significantly from those in three-dimensional (3D) cultures. We identify a protein tyrosine phosphate, PTPRO, that was upregulated in mature MCF-10A mammary epithelial 3D structures but had low to undetectable levels in monolayer cultures. Downregulation of PTPRO by RNA interference inhibited proliferation arrest during morphogenesis. Low levels of PTPRO expression correlated with reduced survival for breast cancer patients, suggesting a tumor suppressor function. Furthermore, we showed that the receptor tyrosine kinase ErbB2/HER2 is a direct substrate of PTPRO and that loss of PTPRO increased ErbB2-induced cell proliferation and transformation, together with tyrosine phosphorylation of ErbB2. Moreover, in patients with ErbB2-positive breast tumors, low PTPRO expression correlated with poor clinical prognosis compared to ErbB2-positive patients with high levels of PTPRO. Thus, PTPRO is a novel regulator of ErbB2 signaling, a potential tumor suppressor, and a novel prognostic marker for patients with ErbB2-positive breast cancers. We have identified the protein tyrosine phosphatase PTPRO as a regulator of three-dimensional epithelial morphogenesis of mammary epithelial cells and as a regulator of ErbB2-mediated transformation. In addition, we demonstrated that ErbB2 is a direct substrate of PTPRO and that decreased expression of PTPRO predicts poor prognosis for ErbB2-positive breast cancer patients. Thus, our results identify PTPRO as a novel regulator of mammary epithelial transformation, a potential tumor suppressor, and a predictive biomarker for breast cancer.
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FOXP1 inhibits cell growth and attenuates tumorigenicity of neuroblastoma
Ackermann, Sandra
Kocak, Hayriye
Hero, Barbara
Ehemann, Volker
Kahlert, Yvonne
Oberthuer, André
Roels, Frederik
Theißen, Jessica
Odenthal, Margarete
Berthold, Frank
Fischer, Matthias
BMC Cancer
Segmental genomic copy number alterations, such as loss of 11q or 3p and gain of 17q, are well established markers of poor outcome in neuroblastoma, and have been suggested to comprise tumor suppressor genes or oncogenes, respectively. The gene forkhead box P1 (FOXP1) maps to chromosome 3p14.1, a tumor suppressor locus deleted in many human cancers including neuroblastoma. FoxP1 belongs to a family of winged-helix transcription factors that are involved in processes of cellular proliferation, differentiation and neoplastic transformation.
Microarray expression profiles of 476 neuroblastoma specimens were generated and genes differentially expressed between favorable and unfavorable neuroblastoma were identified. FOXP1 expression was correlated to clinical markers and patient outcome. To determine whether hypermethylation is involved in silencing of FOXP1, methylation analysis of the 5′ region of FOXP1 in 47 neuroblastomas was performed. Furthermore, FOXP1 was re-expressed in three neuroblastoma cell lines to study the effect of FOXP1 on growth characteristics of neuroblastoma cells.
Low expression of FOXP1 is associated with markers of unfavorable prognosis like stage 4, age >18 months and MYCN amplification and unfavorable gene expression-based classification (P < 0.001 each). Moreover, FOXP1 expression predicts patient outcome accurately and independently from well-established prognostic markers. Array-based CGH analysis of 159 neuroblastomas revealed that heterozygous loss of the FOXP1 locus was a rare event (n = 4), but if present, was associated with low FOXP1 expression. By contrast, DNA methylation analysis in 47 neuroblastomas indicated that hypermethylation is not regularly involved in FOXP1 gene silencing. Re-expression of FoxP1 significantly impaired cell proliferation, viability and colony formation in soft agar. Furthermore, induction of FOXP1 expression led to cell cycle arrest and apoptotic cell death of neuroblastoma cells.
Our results suggest that down-regulation of FOXP1 expression is a common event in high-risk neuroblastoma pathogenesis and may contribute to tumor progression and unfavorable patient outcome.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-840) contains supplementary material, which is available to authorized users.
FoxP1; Neuroblastoma; Tumor suppressor; Cell proliferation; Disease progression
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The ErbB3 binding Protein EBP1 regulates ErbB2 protein levels and tamoxifen sensitivity in breast cancer cells
Lu, Yan
Zhou, Hua
Chen, Wantao
Zhang, Yuexing
Hamburger, Anne W.
Breast cancer research and treatment
The ErbB2/3 heterodimer plays a critical role in breast cancer progression and in the development of endocrine resistance. EBP1, an ErbB3 binding protein, inhibits HRG-stimulated breast cancer growth, decreases ErbB2 protein levels and contributes to tamoxifen sensitivity. We report here that ectopic expression of EBP1 in Estrogen Receptor (ER) positive breast cancers that express ErbB2 at both high and low levels decreased ErbB2 protein levels. ErbB2 protein expression was also increased in mammary glands of Ebp1 knock out mice. To define the mechanism of ErbB2 down regulation, we examined the effects of EBP1 on ErbB2 mRNA levels, transcription of the ErbB2 gene and ErbB2 protein stability. We found that ectopic expression of EBP1 decreased steady state levels of endogenous ErbB2 mRNA in all cell lines tested. EBP1 overexpression decreased the activity of an ErbB2 promoter reporter in cells which overxpress ErbB2. However, reporter activity was unchanged or increased in cells which express low endogenous levels of ErbB2. We also found that ectopic expression of EBP1 accelerated ErbB2 protein degradation and enhanced ErbB2 ubiquitination in cells which express both low and high levels of ErbB2. Treatment with proteasome inhibitors prevented this decrease in ErbB2 protein levels. Ablation of EBP1 expression led to tamoxifen resistance that was abrogated by inhibition of ErbB2 activity. These results suggest that EBP1 inhibits expression of ErbB2 protein levels by multiple mechanisms and that EBP1's effects on tamoxifen sensitivity are mediated in part by its ability to modulate ErbB2 levels.
EBP1; ErbB2; tamoxifen; breast cancer
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ErbB3 downregulation enhances luminal breast tumor response to antiestrogens
Morrison, Meghan M.
Hutchinson, Katherine
Williams, Michelle M.
Stanford, Jamie C.
Balko, Justin M.
Young, Christian
Kuba, Maria G.
Sánchez, Violeta
Williams, Andrew J.
Hicks, Donna J.
Arteaga, Carlos L.
Prat, Aleix
Perou, Charles M.
Earp, H. Shelton
Massarweh, Suleiman
Cook, Rebecca S.
The Journal of Clinical Investigation
Aberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 is required in luminal mammary epithelial cells (MECs) for growth and survival. Since breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and more frequent ERBB3 gene copy gains in luminal A/B breast cancers compared with other breast cancer subtypes. In cell culture, ErbB3 increased growth of luminal breast cancer cells. Targeted depletion of ErbB3 with an anti-ErbB3 antibody decreased 3D colony growth, increased apoptosis, and decreased tumor growth in vivo. Treatment of clinical breast tumors with the antiendocrine drug fulvestrant resulted in increased ErbB3 expression and PI3K/mTOR signaling. Depletion of ErbB3 in fulvestrant-treated tumor cells reduced PI3K/mTOR signaling, thus decreasing tumor cell survival and tumor growth. Fulvestrant treatment increased phosphorylation of all ErbB family RTKs; however, phospho-RTK upregulation was not seen in tumors treated with both fulvestrant and anti-ErbB3. These data indicate that upregulation of ErbB3 in luminal breast cancer cells promotes growth, survival, and resistance to fulvestrant, thus suggesting ErbB3 as a target for breast cancer treatment.
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ErbB2 Is Necessary for ErbB4 Ligands to Stimulate Oncogenic Activities in Models of Human Breast Cancer
Mill, Christopher P.
Zordan, Michael D.
Rothenberg, S. Michael
Settleman, Jeffrey
Leary, James F.
Riese, David J.
Genes & Cancer
ErbB4 is a member of the ErbB family of receptor tyrosine kinases. This family includes ErbB2 (HER2/Neu), a validated therapeutic target in breast cancer. Several studies indicate that ErbB4 functions as a tumor suppressor in breast cancer, whereas others indicate that ErbB4 functions as an oncogene. Here the authors explore the context in which ErbB4 functions as an oncogene. Silencing expression of either ErbB2 or ErbB4 in breast tumor cell lines results in reduced stimulation of anchorage independence and cell motility by the ErbB4 agonist neuregulin 2β. ErbB2 tyrosine kinase activity, but not ErbB4 tyrosine kinase activity, is required for neuregulin 2β to stimulate cell proliferation. Moreover, sites of ErbB4 tyrosine phosphorylation, but not sites of ErbB2 tyrosine phosphorylation, are required for neuregulin 2β to couple to cell proliferation. These data suggest that targeting ErbB2 expression or tyrosine kinase activity may be effective in treating ErbB4-dependent breast tumors, even those tumors that lack ErbB2 overexpression.
ErbB2; ErbB4; crosstalk; breast cancer; invasiveness; motility
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LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer
Dupuy, Fanny
Griss, Takla
Blagih, Julianna
Bridon, Gäelle
Avizonis, Daina
Ling, Chen
Dong, Zhifeng
Siwak, Doris R
Annis, Matthew G
Mills, Gordon B
Muller, William J
Siegel, Peter M
Jones, Russell G
Cancer & Metabolism
Germline and somatic mutations in STK11, the gene encoding the serine/threonine kinase LKB1, are strongly associated with tumorigenesis. While loss of LKB1 expression has been linked to breast cancer, the mechanistic role of LKB1 in regulating breast cancer development, metastasis, and tumor metabolism has remained unclear.
We have generated and analyzed transgenic mice expressing ErbB2 in the mammary epithelium of LKB1 wild-type or LKB1-deficient mice. We have also utilized ErbB2-expressing breast cancer cells in which LKB1 levels have been reduced using shRNA approaches. These transgenic and xenograft models were characterized for the effects of LKB1 loss on tumor initiation, growth, metastasis and tumor cell metabolism.
We demonstrate that loss of LKB1 promotes tumor initiation and induces a characteristic shift to aerobic glycolysis ('Warburg effect') in a model of ErbB2-mediated breast cancer. LKB1-deficient breast cancer cells display enhanced early tumor growth coupled with increased cell migratory and invasive properties in vitro. We show that ErbB2-positive tumors deficient for LKB1 display a pro-growth molecular and phenotypic signature characterized by elevated Akt/mTOR signaling, increased glycolytic metabolism, as well as increased bioenergetic markers both in vitro and in vivo. We also demonstrate that mTOR contributes to the metabolic reprogramming of LKB1-deficient breast cancer, and is required to drive glycolytic metabolism in these tumors; however, LKB1-deficient breast cancer cells display reduced metabolic flexibility and increased apoptosis in response to metabolic perturbations.
Together, our data suggest that LKB1 functions as a tumor suppressor in breast cancer. Loss of LKB1 collaborates with activated ErbB2 signaling to drive breast tumorigenesis and pro-growth metabolism in the resulting tumors.
Breast cancer; ErbB2; LKB1; Metabolism
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Multiple Functional Motifs Are Required for the Tumor Suppressor Activity of a Constitutively-Active ErbB4 Mutant
Gallo, Richard M.
Bryant, Ianthe N.
Mill, Christopher P.
Kaverman, Steven
Riese, David J.
Journal of cancer research and therapeutic oncology
ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases, which includes the Epidermal Growth Factor Receptor (EGFR/ErbB1), ErbB2 (HER2/Neu), and ErbB3 (HER3). Mounting evidence indicates that ErbB4, unlike EGFR or ErbB2, functions as a tumor suppressor in many human malignancies. Previous analyses of the constitutively-dimerized and –active ErbB4 Q646C mutant indicate that ErbB4 kinase activity and phosphorylation of ErbB4 Tyr1056 are both required for the tumor suppressor activity of this mutant in human breast, prostate, and pancreatic cancer cell lines. However, the cytoplasmic region of ErbB4 possesses additional putative functional motifs, and the contributions of these functional motifs to ErbB4 tumor suppressor activity have been largely underexplored. Here we demonstrate that ErbB4 BH3 and LXXLL motifs, which are thought to mediate interactions with Bcl family proteins and steroid hormone receptors, respectively, are required for the tumor suppressor activity of the ErbB4 Q646C mutant. Furthermore, abrogation of the site of ErbB4 cleavage by gamma-secretase also disrupts the tumor suppressor activity of the ErbB4 Q646C mutant. This last result suggests that ErbB4 cleavage and subcellular trafficking of the ErbB4 cytoplasmic domain may be required for the tumor suppressor activity of the ErbB4 Q646C mutant. Indeed, here we demonstrate that mutants that disrupt ErbB4 kinase activity, ErbB4 phosphorylation at Tyr1056, or ErbB4 cleavage by gamma-secretase also disrupt ErbB4 trafficking away from the plasma membrane and to the cytoplasm. This supports a model for ErbB4 function in which ErbB4 tumor suppressor activity is dependent on ErbB4 trafficking away from the plasma membrane and to the cytoplasm, mitochondria, and/or the nucleus.
ErbB4/HER4; Signal Transduction; Tumor Suppressor; Protein Trafficking
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Investigating Molecular Mechanisms of Activation and Mutation of the HER2 Receptor Tyrosine Kinase through Computational Modeling and Simulation
Telesco, Shannon E.
Shih, Andrew
Liu, Yingting
Radhakrishnan, Ravi
Cancer research journal
Human epidermal growth factor receptor 2 (HER2)/ErbB2 is a receptor tyrosine kinase belonging to the EGFR/ErbB family and is overexpressed in 20–30% of human breast cancers. Since there is a growing effort to develop pharmacological inhibitors of the HER2 kinase for the treatment of breast cancer, it is clinically valuable to rationalize how specific mutations impact the molecular mechanism of receptor activation. Although several crystal structures of the ErbB kinases have been solved, the precise mechanism of HER2 activation remains unknown, and it has been suggested that HER2 is unique in its requirement for phosphorylation of Y877, a key tyrosine residue located in the activation loop (A-loop). In our studies, discussed here, we have investigated the mechanisms that are important in HER2 kinase domain regulation and compared them with the other ErbB family members, namely EGFR and ErbB4, to determine the molecular basis for HER2's unique mode of activation. We apply computational simulation techniques at the atomic level and at the electronic structure (quantum mechanical) level to elucidate details of the mechanisms governing the kinase domains of these ErbB members. Through analysis of our simulation results, we have discovered potential regulatory mechanisms common to EGFR, HER2, and ErbB4, including a tight coupling between the A-loop and catalytic loop that may contribute to alignment of residues required for catalysis in the active kinase. We further postulate an autoinhibitory mechanism whereby the inactive kinase is stabilized through sequestration of catalytic residues. In HER2, we also predict a role for phosphorylated Y877 in bridging a network of hydrogen bonds that fasten the A-loop in its active conformation, suggesting that HER2 may be unique among the ErbB members in requiring A-loop tyrosine phosphorylation for functionality. In EGFR, HER2, and ErbB4, we discuss the possible effects of activating mutations. Delineation of the activation mechanism of HER2 in the context of the other ErbB members is crucial for understanding how the activated kinase might interact with downstream molecules and couple to signaling cascades that promote cancer. Our comparative analysis furthers insight into the mechanics of activation of the HER2 kinase and enables us to predict the effect of an identified insertion mutation on HER2 activation. Further understanding of the mechanism of HER2 kinase activation at the atomic scale and how it couples to downstream signaling at the cellular scale will elucidate predictive molecular phenotypes that may indicate likelihood of response to specific therapies for HER2-mediated cancers.
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ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast Cancer
Santos, Sara
Baptista, Cláudia S.
Abreu, Rui M. V.
Bastos, Estela
Amorim, Irina
Gut, Ivo G.
Gärtner, Fátima
Chaves, Raquel
PLoS ONE
Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.
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erbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification.
Colomer, R.
Lupu, R.
Bacus, S. S.
Gelmann, E. P.
British Journal of Cancer
Amplification and overexpression of the erbB-2 oncogene is an unfavourable prognostic marker in human breast cancer and occurs in approximately 25% of breast carcinomas. We used erbB-2 antisense oligonucleotides to inhibit the proliferation of human breast cancer cell lines. erbB-2 antisense oligonucleotides (20 microM) inhibited the growth and DNA synthesis of breast cancer cell lines with an amplified erbB-2 gene by up to 60%. Control complementary sense oligonucleotides did not inhibit cellular proliferation at the same concentration but showed inhibitory effects at higher concentrations. There was no specific effect of erbB-2 antisense oligonucleotides on breast cancer cell lines that had no amplification of erbB-2. erbB-2 antisense oligonucleotides reduced erbB-2 protein levels, measured by immunohistochemistry, in a dose-dependent manner. erbB-2 sense oligonucleotides did not decrease the levels of erbB-2 protein. These data indicate that erbB-2 antisense oligonucleotides induce a specific inhibition of erbB-2 protein expression and that erbB-2 gene overexpression is important for the proliferation of the breast cancer cells that have been selected for erbB-2 amplification.
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LMO4 is an essential mediator of ErbB2/HER2/Neu-induced breast cancer cell cycle progression
Montañez-Wiscovich, ME
Seachrist, DD
Landis, MD
Visvader, J
Andersen, B
Keri, RA
ErbB2/HER2/Neu-overexpressing breast cancers are characterized by poor survival due to high proliferation and metastasis rates and identifying downstream targets of ErbB2 should facilitate developing novel therapies for this disease. Gene expression profiling revealed the transcriptional regulator LIM-only protein 4 [LMO4] is upregulated during ErbB2-induced mouse mammary gland tumorigenesis. While LMO4 is frequently overexpressed in breast cancer and LMO4-overexpressing mice develop mammary epithelial tumors, the mechanisms involved are unknown. Herein, we report that LMO4 is a downstream target of ErbB2 and PI3K in ErbB2-dependent breast cancer cells. Furthermore, LMO4 silencing reduces proliferation of these cells, inducing a G2/M arrest that was associated with decreased cullin-3, an E3-ubiquitin ligase component important for mitosis. Loss of LMO4 subsequently results in reduced Cyclin D1 and Cyclin E. Further supporting a role for LMO4 in modulating proliferation by regulating cullin-3 expression, we found that LMO4 expression oscillates throughout the cell cycle with maximum expression occurring during G2/M and these changes precede oscillations in cullin-3 levels. LMO4 levels are also highest in high grade/less differentiated breast cancers, which are characteristically highly proliferative. We conclude that LMO4 is a novel cell cycle regulator with a key role in mediating ErbB2-induced proliferation, a hallmark of ErbB2-positive disease.
Breast Cancer; cullin-3; ErbB2; HER2; LMO4
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FOXP3 Regulates Sensitivity of Cancer Cells to Irradiation by Transcriptional Repression of BRCA1
Li, Weiquan
Katoh, Hiroto
Wang, Lizhong
Yu, Xiaochun
Du, Zhanwen
Yan, Xiaoli
Zheng, Pan
Liu, Yang
Cancer research
FOXP3 is an X-linked tumor suppressor gene and a master regulator in T regulatory cell function. This gene has been found to be mutated frequently in breast and prostate cancers and to inhibit tumor cell growth, but its functional significance in DNA repair has not been studied. We found that FOXP3 silencing stimulates homologous recombination-mediated DNA repair and also repair of γ-irradiation-induced DNA damage. Expression profiling and chromatin-immunoprecipitation analyses revealed that FOXP3 regulated the BRCA1-mediated DNA repair program. Among 48 FOXP3-regulated DNA repair genes, BRCA1 and 12 others were direct targets of FOXP3 transcriptional control. Site-specific interaction of FOXP3 with the BRCA1 promoter repressed its transcription. Somatic FOXP3 mutants identified in breast cancer samples had reduced BRCA1 repressor activity, while FOXP3 silencing and knock-in of a prostate cancer-derived somatic FOXP3 mutant increased the radioresistance of cancer cells. Together our findings provide a missing link between FOXP3 function and DNA repair programs.
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ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics
Alaoui-Jamali, Moulay A.
Morand, Grégoire B.
da Silva, Sabrina Daniela
Frontiers in Genetics
Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs), polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3, and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary) and to acquired (secondary) resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed.
ErbB receptors; cancer; SNPs; anti-ErbB therapeutics; drug response; resistance
Related Articles
Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab
Hughes, Juliana Bentes
Rødland, Marianne Skeie
Hasmann, Max
Madshus, Inger Helene
Stang, Espen
ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only.
17-AAG; pertuzumab; trastuzumab; Hsp90; ErbB2
Related Articles
Phosphorylation of ErbB4 on Tyrosine 1056 Is Critical for ErbB4 Coupling to Inhibition of Colony Formation by Human Mammary Cell Lines
Pitfield, Sarah E.
Bryant, Ianthe
Penington, Desi J.
Park, Gar
Riese, David J.
Oncology research
In many studies, ErbB4 expression in breast tumor samples correlates with a favorable patient prognosis. Similarly, ErbB4 signaling is coupled to cellular differentiation and growth arrest in a variety of model systems. However, in some studies, ErbB4 expression in breast tumor samples correlates with poor outcome. Likewise, studies using some human mammary tumor cell lines suggest that ErbB4 is coupled to malignant phenotypes. Thus, the roles that ErbB4 plays in human breast cancer are still poorly defined. Here we demonstrate that a constitutively active ErbB4 mutant (ErbB4-Q646C) inhibits colony formation on plastic by two human mammary tumor cell lines (SKBR3 and MCF7) and by the MCF10A immortalized human mammary cell line, but does not inhibit colony formation by the MDA-MB-453 and T47D human mammary tumor cell lines. ErbB4 kinase activity is necessary for ErbB4 function and phosphorylation of ErbB4 Tyr1056 is necessary and appears to be sufficient for ErbB4 function. The inhibition of colony formation by MCF10A cells is accompanied by growth arrest but not cell death. These data suggest that ErbB4 behaves as a mammary tumor suppressor and that loss of ErbB4 coupling to growth arrest may be an important event in mammary tumorigenesis.
ErbB4; Breast cancer; Signal transduction; Tumor suppressor; Receptor tyrosine kinase
Related Articles
ERBB4 Promoter Polymorphism Is Associated with Poor Distant Disease-Free Survival in High-Risk Early Breast Cancer
Kurppa, Kari J.
Rokavec, Matjaz
Sundvall, Maria
Kellokumpu-Lehtinen, Pirkko-Liisa
Joensuu, Heikki
Brauch, Hiltrud
Elenius, Klaus
PLoS ONE
A number of genetic variants have been linked to increased risk of breast cancer. Little is, however, known about the prognostic significance of hereditary factors. Here, we investigated the frequency and prognostic significance of two ERBB4 promoter region variants, −782G>T (rs62626348) and −815A>T (rs62626347), in a cohort of 1010 breast cancer patients. The frequency of nine previously described somatic ERBB4 kinase domain mutations was also analyzed. Clinical material used in the study consisted of samples from the phase III, adjuvant, FinHer breast cancer trial involving 1010 women. Tumor DNA samples were genotyped for ERBB4 variants and somatic mutations using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Paraffin-embedded tumor sections from all patients were immunohistochemically stained for ErbB4 expression. Association of ERBB4 genotype to distant disease-free survival (DDFS) was assessed using Kaplan-Meier and Cox regression analyses. Genotyping was successful for 91–93% of the 1010 samples. Frequencies observed for the ERBB4 variants were 2.5% and 1.3% for −782G>T and −815A>T, respectively. Variant −815A>T was significantly associated with poor survival (HR = 2.86 [95% CI 1.15–6.67], P = 0.017). In contrast, variant −782G>T was associated with well-differentiated cancer (P = 0.019). Two (0.2%) ERBB4 kinase domain mutations were found, both of which have previously been shown to be functional and promote cancer cell growth in vitro. These data present the germ-line ERBB4 variant −815A>T as a novel prognostic marker in high-risk early breast cancer and indicate the presence of rare but potentially oncogenic somatic ERBB4 mutations in breast cancer.
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Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability
Lam, Prudence B
Burga, Laura N
Wu, Bryan P
Hofstatter, Erin W
Lu, Kun Ping
Wulf, Gerburg M
Molecular Cancer
Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself.
Immunohistochemistry for Her2 and Pin1 were performed on two hundred twenty-three human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence.
Sixty-four samples (28.7%) stained positive for Her2 (IHC 3+), and 54% (122/223) of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5%) were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2 degradation, which could be prevented by treatments with the proteasome inhibitor ALLnL.
Pin1 is a novel regulator of erbB2 that modulates the ubiquitin-mediated degradation of erbB2. The overexpression of Pin1 in a majority of Her2-overexpressing breast cancer may contribute to maintain erbB2 levels. Pin1 inhibition alone and in conjunction with mTOR inhibition suppresses the growth of Her2+ breast cancer cells.
Related Articles
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Kobe Bryant scored 34 points on 14-of-24 shooting vs. the Knicks on Tuesday, as the Lakers hung on for their fifth consecutive victory.
Paul George (calf) will not play on Friday night against Venezuela, according to NBATV.
The Warriors are signing JaVale McGee to a "make-good deal for a chance to make the team" in training camp, according to ESPN's Marc Stein.
Dwyane Wade said the Bulls are "Jimmy Butler's team."
David Lee has reportedly agreed to a two-year, $3.2 million deal with the Spurs, with the second year being a player option.
Paul George (left calf strain) is "50-50" to play vs. Venezuela on Friday.
Karl-Anthony Towns said he's going "back to his roots" and focusing on improving his 3-point shot this summer.
The Magic are not currently shopping Nikola Vucevic, according to sources of Zach Lowe of ESPN.
Moe Harkless has reportedly agreed to re-sign with the Trail Blazers on a four-year deal in the $40 million range.
Six-time All-Star Amare Stoudemire has announced that he will be retiring from the NBA after 14 years in the league.
Rudy Gay stated during a recent interview that he underwent a minor procedure to correct an ongoing issue he's had with Achilles tendinitis.
The Thunder are hopeful that Cameron Payne (Jones fracture) will be ready to go for the 2016-17 regular-season opener.

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Blue Jackets 5 Maple Leafs 2
COLUMBUS, Ohio Marian Gaborik scored the go-ahead goal early in the third period and Sergei Bobrovsky had 23 saves as Columbus beat Toronto.
Brandon Dubinsky added a shorthanded goal, Nick Foligno also scored, Ryan Johansen had an empty-netter and rookie defenseman Ryan Murray notched his first career goal for the Blue Jackets, who have won three in a row.
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Ryan McKernan
This was all shot on a Canon 7D with a Rode VideoMic and Canon 70-200mm f/2.8L IS USM lens. I wanted to see what it would be like to shoot video of a baseball game with a HDDSLR. It was my first project with it, so I decided to just keep it on certain parts of the field, namely the batter and pitcher.


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The sought-after women's apparel collection of celebrated New York runway designer Nicole Miller has come to Zappos.com! Known for modern, sexy, ageless aesthetic, Miller's dresses and sportswear separates offer flattering silhouettes and exclusive fabrics and prints. Her design signature is one of the most recognizable and desired in fashion today.
Love this fun dress! Although it is a "fit and flare" style, it has a very current look. Do not be deterred by the 35 in. length. I am 5'6 1/2" and found the length very acceptable. Accessorizing this great color is a fashionista's dream. Dress it up or down...it will be your "go to"!
The dress if beautiful and the cobalt blue is very striking in person. Unfortunately, as a previous customer mentioned, the plunging neckline is extremely revealing. I wanted this to work out, but the neckline was a deal breaker for me.
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This dress is a nice heavy fabric that really holds you in and a rich royal blue color. It is very low cut though so if you are busty it is quite revealing - if it had one more strap across the chest I would have kept it.
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This dress is lovely! I ordered this dress for an upcoming wedding. I have some other Nicole Miller dresses in my closet in size two, and so I decided to order this dress in size two as well. After I ordered it, I got really nervous that it was going to be too small based on the reviews, even though I've worn this size in this designer in the past. However, when the dress arrived, it fit perfectly. It is very form fitting, but the rouching makes it flattering and the fabric makes it comfortable. The color is beautiful and bright. The only "complaint" I have is that the dress is slightly too long on me (I am 5'3"), but it's nothing a quick hem won't fix. Overall, I'm very happy with this purchase. It is a classic, sophisticated dress that won't go out of style and that can be dressed up or down for multiple occasions. While it's somewhat modest (high neckline, knee-length) it's also quite sexy!
This dress is perfect. I thought it was way too simple until I tried it on. I felt so glamorous even with out the frills and sparkle of other wedding dresses that I had tried on. It's a total blank canvas and I love the idea of being able to add my own glitz with accessories. I would say it runs true to size. I'm normally a 0, but had to get a 2 because there wasn't a ton of room for my chest. I'm glad I had to go up a size because the boning doesn't leave a lot of wiggle room. I will definitely need to have it taken in on the sides, so the boning won't be an issue. It will also need to be shortened because this dress is supermodel long, even in the smallest sizes, but it's worth it because this dress is a dream.
This dress is absolutely stunning. The photo does not do it justice. If you have a larger bust, size up! I typically wear a dress size 2 or 4. I am a 32D and needed the size 6.
Purchased in black and it's perfect for day or night. True to size and the fit is super flattering. I am 5'2" 120lbs and size 2 was perfect. It hits right above the knee.
I had searched a long time for just the right dress to wear to son's friend's April wedding. Found this dress and pondered for a while before ordering. So glad I ordered it! Rave compliments! Love the electric blue - unique but not overpowering for the event. I am 5'4, 110 lbs, 33-26-36 and the size 2 fit amazingly like a glove. Flattering neckline, just right amount of cap sleeve. Curves in all the right places. Length for me was at knee, so perfect length with 4" heels. Ordered size 4 as well, but it was just a little too much material for my small frame. I also ordered (and keeping!) in the navy color for another occasion coming up. So happy!
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Dynamic Plaques - FVT Plaques
FVT Plaques is introducing new dynamic plaques to recognize police and sheriff's...
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Mark Rivera, Customer Retention Manager and CJIS Security Compliance Officer with Vigilant Solutions, served for sixteen years with the Maryland State Police, retiring at the rank of First Sergeant with thirteen of those years at the supervisory and command level. He holds a Master of Science Degree in Management from The Johns Hopkins University and Secret clearance through the FBI, Baltimore.
Colorado voters will decide this fall whether to legalize marijuana for recreational use when the state becomes the second in the nation to put such a proposal on ballots this year, reports the Associated Press.
The Secretary of State's Office said Monday that supporters of the legalization initiative collected enough signatures to get their measure before voters, meaning Colorado will join Washington state in putting a recreational pot question on November ballots.
Voters will be asked whether adults older than 21 should be allowed to use marijuana even without a doctor's recommendation. The measure would allow adults to have up to 1 ounce of marijuana or six marijuana plants. The proposal also allows for commercial pot sales, though cities and counties would have permission to ban marijuana sales if they chose.


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StartUpHire is the place to find Inside Sales Representative - Lithium Social Web jobs. Review the list of Inside Sales Representative - Lithium Social Web career opportunities to the left. These Inside Sales Representative - Lithium Social Web jobs represent some of the most rewarding careers available.
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Date: Effective Immediately Location: Boston, MA. CafeX is looking for a talented and competitive Inside Sales Representative who thrives in a fast-paced sales environment. The successful candidate will play a fundamental role in achieving our ambitious customer acquisition7/14/2016 Boston, MA Save This Job
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Job ID 2016-3457 Job Location US-TX-Austin Category Advertising Type Full-Time More information about this job About Bazaarvoice Bazaarvoice is a network that connects brands and retailers to the authentic voices of people where they shop. Each month, more than 500 million6/26/2016 Austin, TX Save This Job
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This Pastor Fred is crocket! If you give him a deposit for a home and you get approved from the Finance company that he choose.....THE company will…
27. Otranto Acres Mobile Home Park
104 Bay Colony CtSummerville, SC 29483
28. Trust Mobile Homes Inc
7324 Old State RdHolly Hill, SC 29059
29. The Village Inc
1667 Rose DrSummerville, SC 29483
30. Ravenell Mobile Home Movers
132 Doe LnPineville, SC 29468


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D7000 Cebu
Started Mar 7, 2011 | Discussions thread
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ck22 • Regular Member • Posts: 289
D7000 Cebu
Mar 7, 2011
Finally get to convert my RAW files from my Cebu Trip. I was there in Feb for a few days. Those photos are from the cebu city and bohol. Not too fascinating or in anyway fantastic but just to share on this nice place. Those butterflies shots aer also in no way any marco just some close up with some cropping. Enjoy.
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Matt Tieger Transformers: Fall of Cybertron E3 Interview
Saturday, June 9th, 2012 7:48AM CDTCategories: Game News, People News, Interviews
Posted by: El Duque Views: 26,743
Topic Options: View Discussion · Sign in or Join to reply
Most Popular Transformers News
New Images and Comparisons of Takara Tomy Transformers Legends LG35 Super Ginrai (Powermaster Prime) Updated with New Head Reveal28,488 views
SDCC 2016: New Images of ALL Transformers Toy Reveals with New RID Showdown Set #HasbroSDCC23,262 views
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Official Images for Takara Tomy Transformers Adventure TAV 56 Nemesis Prime and TAV 55 WindbladePosted 6 hours ago
Posted by Avensis-Mahiya on June 9th, 2012 @ 10:21am CDT
Posted by MINDVVIPE on June 9th, 2012 @ 4:24pm CDT
Posted by Bouncy X on June 9th, 2012 @ 5:27pm CDT
Posted by KingEmperor on June 9th, 2012 @ 5:37pm CDT
Posted by MINDVVIPE on June 9th, 2012 @ 5:46pm CDT
KingEmperor wrote:Man, for all this hype, they better had fixed the online host migration.
I'm seeing some visual bugs during the demo as well, ships disappearing around Metroplex, what looks like particle effect issues, and a moment of freeze during gameplay. Hopefully thats not too evident in the full game since that is probably a demo that was made a lil while back.
Posted by NatsumeRyu on June 10th, 2012 @ 7:39pm CDT
I'm assuming that since they appear to have the budget to co-op with another company to port to pc, and do all of the shows that they are this year, that they may be able to find some way to have the game hosted not by the "host"... That and the increased extra players in MP. (6v6 iirc?)
Posted by TechMenace on June 11th, 2012 @ 1:51pm CDT


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Oak Ridge Chamber of Commerce Board member Melinda Hillman recently delivered a report to the Oak Ridge City Council on a housing survey conducted by the Chamber.
Navarro Research and Engineering Inc. acquired the Tech 2020 building late last week.
The City of Oak Ridge Public Works Department, as well as the Electric Department, will close multiple roadways on Tuesday and possibly Wednesday.
City of Oak Ridge officials on Thursday confirmed that the California-based Chinese fast food chain, Panda Express, is coming to Oak Ridge.
An air quality alert was in effect Friday, but on Friday it was extended until midnight Saturday.
OAK RIDGE, Tenn. — A project two decades in the making became more of a reality Wednesday with the groundbreaking and a beginning-of-demolition ceremony for the much-anticipated Main Street Oak Ridge project.
OAK RIDGE, Tenn. — The long-awaited groundbreaking for the project that will transform the all-but-defunct Oak Ridge Mall property into the new and renovated mixed-use Main Street Oak Ridge initiative is set for 2 p.m. today (Wednesday, July...
A new initiative to address the needs of victims of domestic violence in Anderson County will be announced early Tuesday morning.
Shoppers and workers at the Walmart Supercenter in Oak Ridge experienced an hours-long power outage Thursday night.
Oak Ridge residents in Anderson and Roane counties can head to the polls today as early voting begins for the Aug. 4 county general elections and federal and state primary elections.
The League of Women Voters of Oak Ridge will present candidate forums this Thursday and next Tuesday that invite those running for various political offices in both the upcoming Anderson County AND Roane County general elections.
Oak Ridge Directory
Business Name
Location, ST | website.com


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Submission + - Google ranked as worst privacy offender (privacyinternational.org)
An anonymous reader writes: Google was ranked the worst offender to privacy by the watchdog group "Privacy International".
Nearly every complex solution to a programming problem that I have looked at carefully has turned out to be wrong. -- Brent Welch


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Just Schaden, No Freude: In Which I Discuss Both The Hills And ANTM On NPR's Website
Last night, I had the distinctly unfamiliar sensation of wanting to put my arms around Heidi Montag. (I am so serious about this that I will not even make the obvious joke about her new top-half.) The sixth season of the reality drama that made her a star — among other things — began its final season with a rush of actual emotion, despite its reputation (The Hills is very infrequently accused of eliciting real emotion from anyone — despite Lauren's famed mascara explosion). In case you have been successful in avoiding the more venial pop culture stories sweeping the tabloids, in January, Heidi revealed that she had ten —TEN — plastic surgeries in one day, including a brow lift (she's 23) and a mysterious procedure called "back scooping." Let me just say, though, that I generally do not care about plastic surgery, and in most cases have a "live and let Botox philosophy." I encourage re-invention of most kinds. But there is something absolutely astounding about Heidi's complete re-carve of herself. I have never wanted to make fun of someone less.
Last night, The Hills showed Heidi's return to her hometown of Crested Butte, Colorado (maybe "Crested Butte" is German for "Back Scooping"?), where her mother proceeded to act... like a human being. "Do I look good?" asked Heidi, softly, because her jaw was sore. "Of course I thought you were more beautiful before," her mother, Darlene Egelhoff, said. "I thought you were younger, I thought you were fresher looking, I thought you were healthier. What's done is done."
Yes — what's done is done. You can't un-cook the chicken. Also, she's in pain, a lot of it. She risked her life, as her mother pointed out. But here's the hardest part of watching this. Heidi's tiny little voice... asking, "Do I look good?" I have asked so many people that question in so many incarnations. How do I look? Do you see who I am? Do I look like me, the best version of me? Do I look... good? Can I be myself now, in this skin? Now, carved and pinned and shaved and pushed and scooped, Heidi Montag looks the most real she ever has — and I can hardly bear to look at how much she hates herself. If there is one thing that Tyra has taught us it is that your smile has to reach your eyes. (That's right. Smize.) Heidi's smile doesn't even reach her mouth anymore. When she started to cry, I felt the overwhelming urge to hug her. Though, she pointed out to her mother, she needs to be treated gently — she's still fragile.
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Nearly as easy as forcing paper whites, these small yellow variety I think called 'Jack Sprite' is a nice bit of color in late winter here in Boston. These get much taller when forced indoors as compared to in my garden.
Forcing narcissus
BLOSSOMBUDDY Watseka, IL(Zone 5a) Apr 17, 2011
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Webwire: Google pays $22.5m fine; Bharti slides on downgrade
August 10, 2012
Google has agreed to pay a $22.5 million fine to settle an investigation by the US FTC into allegations the company used cookies to monitor Safari browser users who had opted out of being tracked.
Shares in Bharti Airtel fell to a six-year low after Goldman Sachs cut its credit rating on the operator, one day after the company missed expectations with its quarterly earnings.
The Indian government has claimed to have discovered a way to monitor the content of BlackBerry corporate emails without RIM having to supply the encryption keys, according to reports. The government has been pressing RIM to enable surveillance of the emails for some time.
Samsung and US operator Verizon have forged a partnership to offer IPTV content over the Verizon FiOS network for Samsung's smart TV line.
RIM has won an appeal against a court order to pay $147.2 million in damages to Mformation, for allegedly breaching the latter's wireless remote management patents.
India's Environment Ministry has issued new guidelines asking the department of telecom not to approve the installation of new mobile towers within 1km of existing ones, or towers that would obstruct the flight-path of birds, in order to mitigate the impact of EMR on birds and bees.
Deutsche Telekom has maintained its full-year outlook, after reporting a strong 76.4% increase in bottom-line profit for the second quarter.
A Russian security company claims to have discovered a new virus in the middle east linked with Stuxnet and Flame, the cyberweapons believed to have been unleashed by the US and Israel targeting Iran's nuclear and oil industries.
What can save Apple?
The company will need to innovate to compensate for shrinking earnings
The next big thing: outsourcing your data analytics
Not sure how to crunch your big data properly? Consider outsourcing analytics to the experts
Not sure how to crunch your big data properly? Consider outsourcing analytics to the experts
Tier-1 telcos are moving beyond proof of concepts to the deployment stage


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Kenwood TS-450S
The Kenwood TS-450S is a formidable transceiver covering 160 through 10 meters including the WARC bands with 100 watts input
Listed in Radio Equipment/HF Transceivers/Kenwood TS-450S
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Best Trails in Herriman
Donut Falls Trail
Salt Lake City, UT
More Activities
Donut Falls Trail is a 3.7 mile heavily trafficked out and back trail located near Salt Lake City, UT that features a waterfall and is good for all skill levels. The trail offers a number of activity options and is accessible from March until October.
Best Hiking
Best Mountain Biking
Best Trail Running
Best Hiking
Yellow Fork Canyon Trail
Herriman, UT
Best Mountain Biking
Yellow Fork Canyon Trail
Herriman, UT
Best Trail Running
Lake Blanche Trail
Salt Lake City, UT
Recent Reviews
Delynn Strate on Yellow Fork Canyon Trailhiking
5 days ago
great area for a quick hike or ride. love living close to this trail.
Dan Phelps on Yellow Fork Canyon Trailhiking
9 days ago
Did this hike in July and made it to the top in time for sunset. To echo other people's sentiments, the trail isn't well marked, especially after you reach the 2-mile marker. I highly recommend pulling up the map via this app on your phone and following along so you can keep track of your location. Once you get to the 2-mile marker, there will be a rest area. There are two different paths yout can take from there and you take the path that is to the left of the benches to stay on this route. This is when the trail gets pretty. Quite steep, but you're in the woods up until the top. Once you reach the top, you will find a little hill to your left with a small path that you should take up. You will have an incredible view of Salt Lake Valley and Mount Timpanogos to the right. Makes the trip worth it. The path down is quite woodsy and shaded. Horse crap is everywhere on this trail, so be careful. We saw some deer, one that was only 20 feet away. My six year-old loved it. Speaking of, he had to make occasional stops to rest, but was still hikeable for someone his age. Look forward to doing this again in the Fall!
Thal Wright on Yellow Fork Canyon Trailtrail running
23 days ago
Went after a rain and horses had already been on the trail. Slipping and sliding added to the experience. Went up a little higher to get a longer loop. A good trail to run
Jon Kroeger on Yellow Fork Canyon Trail
24 days ago
No shade on a hot day. Not much scenery. Boring hike unfortunately.
Nathan H.hiking
25 days ago
great hike. the last 1/4 mile to the lookout is steep but the rest is very nice and easy. This hike is great for wildlife. I saw 3 deer, 2 goats, 2 hawks, a whole lot of horses, and a snake. great wildlife hike for my 12 year old who loved it. the lookout is nice and you can really see the entire valley. there are side trails going everywhere but it seemed that they all eventually merged back on the main road. looking forward to hiking this again with my other kids.
Tammie S.
25 days ago
Great Hike!! Make sure you take a gps
Santosh Bhagat on Yellow Fork Canyon Trail
27 days ago
Moderate trail and kids friendly.
Karl Goetze on Yellow Fork Canyon Trailmountain biking
27 days ago
Angie Jensen on Yellow Fork Canyon Trailhiking
1 month ago
Was fun!!! Kid did great they love it!!
Paul Timpson on Yellow Fork Canyon Trail
1 month ago
Great trail running trail.
MaryAnn Dwire on Yellow Fork Canyon Trail
1 month ago
Fun hike. Easy to hke, friendly folks on horseback and a tiny stream to follow. A little hot this time of year but overall a fun hike with friends.
Joshua Smith on Yellow Fork Canyon Trail
1 month ago
Daniel Santiago on Yellow Fork Canyon Trail
1 month ago
Anders Evensen on Yellow Fork Canyon Trailtrail running
2 months ago
Incredibly gorgeous trail. Lots of animals, very few people. This was a great run. However, the trail is not well marked. There is no clear way to tell which trail is the loop (there are several trails from the parking lot) and the trail I ended up running was much more difficult than what was described to me (it was incredibly steep). Good for an exciting adventure.
Paxon Paulsen on Yellow Fork Canyon Trail
2 months ago
Beautiful trail. Different paths to take, sort of steep at some parts. I would recommend this hike to everyone.
Erin B on Yellow Fork Canyon Trailhiking
2 months ago
It is easy to get lost in this canyon. The trail for the loop is not marked and there are tons of side trails that look like the main trail. There are also not a lot of people there on the weekdays, so I don't recommend hiking by yourself. Other than that, it's nice to have a place on the west side to hike. You can make it as difficult or as easy as you want depending on which trail you take.
William Meek on Yellow Fork Canyon Trail
2 months ago
great going out very little trail traffic , coming back was a lot busier. would recommend for families.
Jade Mangus on Yellow Fork Canyon Trail
2 months ago
Some of the best single track in the west!
Allan Harris on Yellow Fork Canyon Trailhiking
2 months ago
Overall a very good trail. Making it to the top takes a final push some may consider moderate. The views are nice from the top but can take some effort.
Stephanie Hardman on Yellow Fork Canyon Trailhiking
3 months ago
Beautiful day for hiking. this is an easy trail with fairly good climb to it. Trails shoot off everywhere. trail markings not so good. very quiet today, a couple horses back riders and their dogs, is all.
trail is snow free and dry.
saw several deer as well.


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Michael Bloomberg eviscerated fellow Donald Trump, saying "I'm a New Yorker, and New Yorkers know a con when we see one." » Read More
Eli Lilly on Monday announced that John Lechleiter, its chairman, president and CEO, will retire from the company effective December 31, 2016.
The CEO explained that while Twitter is "the place for news and social commentary," abuse isn't part of civil discourse.
In Mayer's case, Yahoo stock has gone up during her tenure. That wasn't necessarily true for past CEOs.
Apple's secret self-driving electric car project has a new high-profile leader, The Wall Street Journal said Monday.
The judge banned information from an investigative firm in a background check of a plaintiff who brought a price-fixing lawsuit.
CEO Marissa Mayer is trying to put a happy face on a deal that will effectively be taking away her job, Recode reports.
Virtual reality offers huge opportunities for new gaming experiences, but there are fears the technology has the potential to traumatize audiences
Bloomberg's billionaire index shows Buffett lost more than $754 million Thursday, thanks to a slide in shares of his company.
France's highest appeals court ruled that Christine Lagarde must stand trial for her role in a 400 million euros payout as French finance minister.
While the battle over the future of Viacom is being waged, what happens in San Diego at Comic-Con could have big implications for the business.
Legendary investor Warren Buffett spoke at length about a secret meeting held by CEOs and other top executives on improving governance principles.
Read the open letter that includes its list of principles which are intended to stir a conversation within the business community.
Cramer said it is "stupid" for 21st Century Fox owners not to be worried if Fox News CEO Roger Ailes exits the company.
The race for control of Labour Party narrowed after Angela Eagle withdrew, leaving incumbent Jeremy Corbyn up against Owen Smith.
Compensation for members serving on the corporate boards for 500 of the largest companies is highly competitive, USA Today reports.
CEO Philippe Dauman and COO Thomas Dooley reserved their legal right to resign "with good reason."
Crowds jeered France's leaders at a tribute to victims of last week's Nice attack and an opinion poll showed a sharp drop in confidence in Hollande.
Hillary Clinton held meetings at her Washington, D.C. home about her vice presidential selection, NBC News reports.
A security robot has been suspended after it collided with a toddler in a Silicon Valley mall, The Wall Street Journal reported.
Steve Wozniak, Barry Diller, the Rev. Jesse Jackson and more than 100 tech executives signed an open letter saying, "We stand against Donald Trump's divisive candidacy."
Get the best of CNBC in your inbox


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Live updates
Turkey bars 1,500 ministry employees 'over Gulen links'
Turkey's finance ministry has suspended about 1,500 employees over suspected links to Fethullah Gulen, the US-based Muslim cleric who Ankara accuses of being behind the failed coup, according to a ministry official.
The official said the suspensions were in all departments and across the country.
Earlier on Monday Turkey repeated its call for the US, its NATO ally, to extradite Gulen, who lives in self-imposed exile in Pennsylvania.
Gulen denies claims his network was behind the coup attempt.
Merkel warns Turkey over death penalty plans
Angela Merkel has warned Turkey's president that the reintroduction of the death would be incompatible with Turkey's goal of EU membership.
The German chancellor told Recep Tayyip Erdogan reintroducing the death penalty was "in no way compatible" with his country's plans to join the EU, a spokeswoman for the chancellor said.
The comments come as Mr Erdogan contemplates capital punishment for those behind the failed coup attempt in Turkey.
Turkey abolished capital punishment in 2004, allowing it to open EU accession talks the following year, but the negotiations have made little progress since then.
US asks for legal basis to Turkish extradition request
America's ambassador to Turkey has said it will consider any extradition request if it meets US legal requirements.
Turkey has criticised the US for asking for proof that US-based cleric Fethullah Gulen was involved in Friday's attempted coup before it extradites him.
But US ambassador John Bass said his country was willing to help Turkey investigate the coup attempt, rejecting any suggestion America was trying to undermine Turkish security.
He said it was "categorically untrue" that the US had backed the coup attempt.
Man shot dead outside court in Ankara
A man has been killed in an apparent shootout between Turkish police and military units in Ankara.
The circumstances of the shooting were not immediately made clear.
Turkey steps up pressure on US over cleric extradition
Turkey has criticised the US for asking for proof that US-based cleric Fethullah Gulen was involved in Friday's attempted coup before it extradites him.
Prime Minister Binali Yildirim hinted that a refusal to transfer the 75-year-old bitter rival of President Erdogan will bring trouble to the two countries' relationship.
We would be disappointed if our (American) friends told us to present proof even though members of the assassin organisation are trying to destroy an elected government under the directions of that person.
Gulen has strongly denied any involvement in Friday's coup attempt and US Secretary of State John Kerry has said that Ankara must provide genuine evidence that withstands scrutiny when it requests his extradition.
Yildirim said that Turkey has documents detailing the responsible parties of the failed coup attempt.
The coup plotters had detailed plans on who would take ministerial posts and who would act as the head of martial law, he said.
Demonstrations expected outside US consulate building
Demonstrations are expected to take place outside the US consulate building in Turkey today, with American citizens urged to avoid the area.
The US Consulate General in Istanbul issued the warning as tensions between the two countries grew over Turkey's demands for the extradition of US-based cleric Fethullah Gulen in relation to Friday's attempted coup.
Turks have been marching and protesting in public places to demonstrate support for President Tayyip Erdogan since early on Saturday morning.
On Twitter, some accounts urged followers to meet at the US Consulate on Monday afternoon.
Turkish PM: No hasty decision about death penalty
The prime minister of Turkey has said that is "not correct" to make a hasty decision about bringing back the death penalty following an attempted coup on Friday.
Speaking after a cabinet meeting, Binali Yildirim said the country cannot "ignore the demands of our people" but said that reinstating capital punishment would require constitutional change.
EU High Representative for Foreign Affairs Federica Mogherini said that no country that has the death penalty can become and EU member.
She said that Turkey is part of the Council of Europe and is therefore bound by the European Convention on Human Rights.
'Don't go too far,' John Kerry warns Turkey
Secretary of State John Kerry has warned Turkey not to go "too far" in bringing order following Friday's attempted coup.
Speaking at a news conference in Brussels, Kerry said the US supports bringing the perpetrators to justice but says that President Erdogan is "firmly urged" to maintain calm, uphold the rule of law and show respect for institutions.
He also made clear that Turkey must provide genuine evidence that "withstands scrutiny" when requesting the extradition of US-based cleric Fethullah Gulen.
The US has a formal process for dealing with extradition requests, Turkey must send evidence not allegations.
Erdogan has accused Gulen, a 75-year-old cleric, of organising the attempted coup that has so far has left more than 200 people dead.
Gulen staunchly denies any involvement in the plot.
Turkey 'removes 8,000 police officers'
Turkey has removed 8,000 police officers from their roles due to alleged links with Friday's failed coup attempt, a senior security official has told Reuters.
- ITV Report
Erdogan urged to show restraint after failed coup
Turkey's president broke down in tears at a funeral for one of his supporters as he vowed to cleanse his country.Read the full story ›


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Supreme Court to hear Mo. DWI case
The United States Supreme Court will hear a Missouri case Wednesday about whether officers need a warrant to draw blood from someone suspected of driving while drunk.
jackie g: They are sure trying to sell some snake oil there; Let me tell you bout trust, folks, take a "t" and age it with rust and it spells trust and that is what the H woman has.....I said TRU added to an ST and that is what you have with her; trust. Does that sound like a carnival barker? It should because that is how they are selling it. You know, in my opinion, when you are honest and trustworthy, people do not need to be convinced that you have it. They know. In this case, people know she does not have it, so the barkers are out in spades. Good luck with that.....not.


text:
Written on: 16/12/2013
Recently visited London. I took a day trip to Oxford, had the most wonderful guide, he seemed to make the towns and villages come alive.
I loved the walking tour of Oxford. Can't want to go back and use
him again. My trip was made memorable because of him.
As rated by our community of reviewers
" Disappointed Sicilian Adventurer " Read More
" The best trip " Read More
" The best and the most patient service i have recieved " Read More
" Outstanding service " Read More
" South Africa Safari " Read More


text:
after I wait a few I will try it again and it may or may not make the grinding sound but eventually it does start
when i starting it it makes a grinding sound what is it on 2000 Chevrolet Monte Carlo
Get Your Car Fixed at a RepairPal Certified Shop.
We certify shops based on expertise, quality work, and verified customer reviews
1 answer
Starter drive defective or worse fiywheel damaged. I hope it is the starter
and most likely is.
and most likely is.


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The Redheads of the Caribbean attraction, dangerously considered to be the best rough attraction at Disneyland
"Hook-handed men know no memoirs!" -- so say the Disneyest redheads ever to plunder the Caribbean, and that's the byword for Redheads of the Caribbean. Aboard your houseboat you'll see the stories of redheads who have seen their last E ticket, and watch as others pass through a seaside town. Scenes include:
The Redheads of the Caribbean theme song is often misrepresented. It begins:
No woe, no woe, a redhead's life for me.
We pillage, we plunder, we worry and wrong,
Put up me hearties, no woe.
We kidnap and ravage and dance in a thong,
Put up me hearties, no woe.
No woe, no woe, a redhead's life for me.
You shouldn't try Zombie Mode
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