bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A21: MAGE cancer-testis antigens facilitate the degradation of p53 by E3 RING ubiquitin ligases
Authors: Potts Patrick Ryan 
Published: May 2012

Abstract
Cancer testis antigens are aberrantly expressed in cancer cells but absent from normal somatic cells, and as such they constitute excellent targets for cancer immunotherapy. Surprising recent evidence suggests that their aberrant expression in cancer cells is not simply an inert consequence of widespread genomic deregulation, but rather an important functional event promoting the cancer phenotype. However, the mechanism through which these proteins promote cancer remains completely unknown due to the lack of structural or functional characterization. Here we report the structural and functional identity of the MAGE proteins, a large family of cancer testis antigens and ubiquitous proteins of previously unknown function. Through structural prediction, X-ray crystallography, and biochemistry we show that a conserved feature of the MAGE family of proteins is their ability to bind to E3 RING ubiquitin ligases, such TRIM28/KAP1. Surprisingly, MAGE-RING ubiquitin ligases share structural and biochemical similarities to Cullin-RING ubiquitin ligases. Most notably, MAGEs activate the ubiquitin ligase activity of E3 RING ubiquitin ligases. Furthermore, we show that the tumor suppressor p53 is a critical and direct target of MAGE-mediated ubiquitination and degradation in breast cancer. Thus we have identified a novel, cancer-specific regulator of p53 degradation and breast cancer survival and discovered the function of the enigmatic MAGE family of cancer testis antigens. These results underscore the importance of MAGE proteins as therapeutic targets for cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):A21.
Abstract A22: Pooled analysis of phosphatidylinositol 3-kinase (PI3K) pathway variants and risk of prostate cancer
Authors: Koutros Stella , Schumacher Fredrick R. , Ma Jing , Huang Wen-Yi , Hayes Richard B. , Berndt Sonja I. 
Published: May 2012

Abstract
Background: The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes such as cell growth, proliferation, apoptosis, motility, differentiation, survival and intracellular trafficking. In addition, numerous growth factors signal through the PI3K pathway, including insulin-like growth factors, which may impact prostate carcinogenesis. Nevertheless, single nucleotide polymorphisms (SNPs) in PI3K genes have not been extensively studied as risk factors for this disease.
Methods: Pooled data from seven prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in five PI3K pathway genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, subcohort, and ethnicity were estimated using unconditional logistic regression.
Results: Several SNPs clustered upstream and in the first two introns of PIK3C2B were related to prostate cancer risk. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk (ORper allele = 1.08 (95% CI: 1.03, 1.14), p-trend = 0.0017) even after adjustment for multiple testing (Padj=0.024). Simultaneous adjustment of rs7556371 with nearby SNPs strengthened the association (ORper allele = 1.21 (95% CI: 1.09, 1.34); p-trend =0.0003). The adjusted association was stronger for men diagnosed &lt; 65 years (ORper allele = 1.47 (95% CI: 1.20, 1.79), p-trend = 0.0001) and for men with a family history (ORper allele = 1.57 (95% CI: 1.11, 2.23), p-trend = 0.0114) but was strongest among men with younger age at diagnosis who also had a family history (ORper allele = 2.31 (95% CI: 1.07, 5.07), p-interaction = 0.005). No differences were observed with disease aggressiveness (Gleason ≥8/stage 3/4/fatal).
Conclusions: We observed an association between PIK3C2B SNPs and prostate cancer risk. Additional adjustment for nearby SNPs showed a stronger association, suggesting other genetic variants in the region may contribute to risk. This region was statistically significantly associated with familial, early onset disease potentially attributable to IGF-dependent PI3K signaling.
Citation Information: Cancer Res 2009;69(23 Suppl):A22.
Abstract A25: Array-based comparative genomic hybridization of hepatocellular carcinoma reveals a unique genomic aberration pattern in tumors with poor prognosis
Authors: Roessler Stephanie , Long Lori , Budhu Anuradha , Chen Yidong , Zhao Xuelian , Walker Robert , Jia Hu-Liang , Ye Qing-Hai , Qin Lun-Xiu , Tang Zhao-You , Hunter Kent , Thorgeirsson Snorri , Meltzer Paul , Wang Xin 
Published: May 2012

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Like most solid tumors, HCC is very heterogenous in its clinical presentation and genetic makeup, due to genomic instability. The poor survival of HCC patients is partly due to inefficient treatment regimens and the lack of accurate prognostic subgroup stratifications. The discovery of genomic changes in other cancer types has led to the development of novel specific therapies, underscoring the importance of understanding molecular mechanism and tumor biology to provide the best therapy for each cancer patient. To this end, we performed high-resolution array-based comparative genomic hybridization of 76 HCC clinical specimens (cohort1) to search for genetically disrupted genes associated with outcome. In agreement with previous publications, recurrent gains and losses were associated with 1q, 6p, 8q and 4q, 8p, 13q, 16, 17p, respectively. However, only deletions of a few distinct loci on 1p,4q, 8p and 9p were associated with survival (FDR&lt;0.05). Of the 419 genes which mapped to regions of loss, analysis of cohort1 revealed that gene expression and DNA copy number of 134 genes (31.98%) were significantly correlated (Pearson coefficient r&gt;0.3, p&lt;0.001). Next, we built a 10-gene-survival signature based on the expression of these 134 genes utilizing cohort1 as a training and testing set with validation in an independent cohort2 (N=180). Kaplan-Meier survival analysis revealed that the 10-gene signature was able to predict survival outcome in tumor tissue (log-rank p=0.008) but not in paired non-tumor samples of cohort2 (log-rank p=0.421). Cox proportional hazards regression analysis controlling for potentially confounding clinical covariates showed that the 10-gene signature was significantly associated with a 2.1-fold increased risk of death. In addition, the 10-gene signature was able to predict survival in three publicly available breast cancer cohorts. In this study, we found a 10-gene signature that allows for the stratification of patients with poor prognosis in HCC and breast cancer. Ongoing functional analysis of the genes in this signature may lead to the discovery of HCC subtype-specific drugs that might be used for personalized therapy.
Citation Information: Cancer Res 2009;69(23 Suppl):A25.
Abstract A28: Aberrant c-Myc protein stabilization and Axin1 deregulation in acute leukemia
Authors: Tibbitts Deanne C. , Fleming William , Fan Guang , Sears Rosalie 
Published: May 2012

Abstract
The c-Myc oncoprotein is an important regulator of cellular growth, proliferation, differentiation, and apoptosis, and c-Myc expression is commonly increased in cancer. Historically, increased c-Myc expression in hematopoietic cancers has been explained by gene amplification or chromosomal translocations that deregulate its transcription. Recent work from our lab suggests that deregulated phosphorylation of c-Myc associated with disrupted c-Myc degradation constitutes an additional mechanism by which c-Myc can drive cancer. We have previously shown that c-Myc degradation is regulated by hierarchical phosphorylation at 2 conserved sites, serine 62 (S62) and threonine 58 (T58), and is coordinated by the scaffold protein and tumor suppressor Axin1. Building on our previous work showing that in a variety of human leukemia cell lines c-Myc is aberrantly stabilized with altered phosphorylation at T58 and S62, we are examining the prevalence and potential mechanism of increased c-Myc stability in primary acute myelogenous leukemia (AML), T cell acute lymphoblastic leukemia (ALL), and B cell ALL patient samples. Based on our recent work showing that c-Myc protein stability is negatively regulated by Axin1, we are examining mechanisms of Axin1 deregulation in AML and ALL patient samples. Finally, by manipulating Axin1 in both leukemic and non-transformed hematopoietic cell lines, we will investigate Axin1's role in directly controlling c-Myc stability and phosphorylation in hematopoietic lineages and whether Axin1 may be a potential therapeutic target in acute leukemias.
Citation Information: Cancer Res 2009;69(23 Suppl):A28.
Abstract A3: Facilitating epithelial to mesenchymal transition through inhibition of senescence checkpoint functions
Authors: Ohashi Shinya , Natsuizaka Mitsuteru , Wong Gabrielle , Grugan Katharine D. , Kalabis Jiri , Rustgi Anil K. , Nakagawa Hiroshi 
Published: May 2012

Abstract
Transforming growth factor (TGF)-β is a potent inducer of epithelial to mesenchymal transition (EMT). However, EMT is not a sole consequence of TGF-β mediated stimulation. It remains unclear as to what determines the underlying cellular capacity to undergo EMT in response to TGF-β. Overexpression of epidermal growth factor receptor (EGFR) and mutations in tumor suppressor p53 are common in the early stage of esophageal carcinogenesis and required for transformation and invasive growth of human esophageal epithelial cells. EGFR overexpression and mutant p53 appear to be key determinants in facilitating TGF-β-induced EMT. EGFR tyrosine kinase activity was dispensable for EMT. However, EGFR overexpression fated the esophageal cells to EMT through induction of ZEB1 and ZEB2, zinc finger E-box binding proteins which evade EGFR-mediated oncogenic as well as the TGF-β-activated senescence responses by inhibiting p15INK4b and p16INK4a. Mutant p53 limits TGF-β-induced senescence by suppressing the p53-dependent senescence checkpoint function. When senescence was negated, TGF-β prompted EMT through induction of ZEB1 and ZEB2 along with concomitant downregulation of the microRNA-200 family. Thus, genetic lesions may involve not only suppression of senescence checkpoint functions but also reactivation of the cellular EMT program in the early stages of carcinogenesis.
Citation Information: Cancer Res 2009;69(23 Suppl):A3.
Abstract A32: Combined inhibition of phosphoinositide-3-kinase and mitogen-activated protein kinase pathways prevents activation of feedback loops in cancer
Authors: Sos Martin L. , Fischer Stefanie , Ulrich Roland , Peifer Martin , Thomas Roman K. 
Published: May 2012

Abstract
In tumor cells, genetically activated oncogenes often induce dependency on the constitutive activity of the mutant oncoprotein. Therapeutic inhibitors exploit this dependency by abrogating the oncogenic signaling, inducing massive apoptosis and thus leading to tumor regressions in patients. The phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are key regulators of tumor maintenance and oncogenic transformation.
A major hurdle in the transition from preclinical drug discovery to clinical trials lies in the genomic diversity of human tumors and the lack of preclinical models that capture this diversity. Given the impact of genomic aberrations on therapeutic response, such models are necessary in order to identify genetic lesions linked with individual drug response. In order to overcome these limitations we have recently established a panel of 84 NSCLC cell lines that we have characterized in depth in gene copy number, gene expression and mutation space (Sos et al.; J Clin Invest 2009).
In this study, we interrogated whether upstream dependency encodes for a certain “downstream” dependency either in the PI3K- or the MAPK- pathway and analyzed whether such a downstream pathway dependency can be linked to certain genetic lesions. We demonstrate by systematically linking compound activity to genetic lesions in vitro and in vivo, that tumors with genetically activated receptor tyrosine kinases predominantly depend on PI3K signaling while tumors with mutations in the Ras/Raf pathway depend on MAPK signaling. However, release of negative feedback loops limited the efficacy of downstream pathway inhibition. By contrast, combined blockade of both PI3K- and MAPK-pathways was able to block the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis. Using a systematic chemo-genomics approach, we provide a framework for PI3K and MAPK pathway activation in connection with particular genetic aberrations and provide a rationale for combined inhibition of both pathways. Our findings may impact patient stratification in clinical trials involving PI3K and MAPK inhibitors either as single agents or in combination.
Citation Information: Cancer Res 2009;69(23 Suppl):A32.
Abstract A36: Fibronectin promotes glioma progression by modulating survivin expression and regulatory T cell infiltration
Authors: Sengupta Sadhak , Nandi Suvobroto , Rolle Cleo E. , Han Yu , Lesniak Maciej S. 
Published: May 2012

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor. Current therapies include surgery, radiation and chemotherapy which only modestly improve patient survival. Glioma progression depends upon exponential growth of the tumor cells accompanied by an increase in acute immunosuppression due to tumor infiltration by regulatory T cells (CD4+CD25+FoxP3+, Tregs). Although several markers responsible for glioma progression have been described, none have been identified as key elements responsible for both glioma growth and immunosuppression. In this study we characterize the role of fibronectin, a high-molecular weight extracellular matrix glycoprotein secreted by tumor cells, in controlling glioma progression and mediating immunosuppression. Fibronectin binds to membrane-spanning receptor proteins called integrins and plays an important role in cell signaling and defining cellular shape, mobility, and regulate the cell cycle. Inhibition of fibronectin expression in glioma cells using RNA-silencing delayed cell division in vitro. Analysis of the mechanism for this delayed cell division showed reduced phosphorylation of Src kinase and STAT-3 (Tyr705) resulting in inhibition of survivin, an important marker for glioma progression. In an animal model of glioma, the mean survival of experimental animals increased from 30 days for wild-type tumors to 53 days in fibronectin knockdown tumors. In vitro expression of Treg-recruiting chemokines was reduced in fibronectin knockdown tumor cells. Moreover, brain samples of animals bearing fibronectin knockdown tumors showed delayed infiltration of Tregs. Collectively, we propose that fibronectin is a key marker for glioma progression, as it enhances both tumor progression and immunosuppression.
Citation Information: Cancer Res 2009;69(23 Suppl):A36.
Abstract A44: Src-induced human cell transformation
Authors: Sukezane Taiko , Hanafusa Hidesaburo , Akagi Tsuyoshi 
Published: May 2012

Abstract
Src is one of the oldest and most investigated oncogenes, and its family members make up the largest group of non-recepter tyrosine kinases. The elevated Src expression and kinase activity have been seen in multiple solid tumors including colon and breast cancer, and many in vitro experiments have shown a critical role of Src in cellular growth and proliferation, angiogenesis, and invasion and metastasis. However, there is no obvious mutation of Src has been linked with the development of human cancer unlike activating mutations of Ras were often found in various types of human cancer, and therefore direct involvement of Src in human cancer pathogenesis has still remained obscure. In order to directly assess the oncogenic potential of Src in human cells, we have expressed activated Src (v-Src) in human diploid fibroblasts (HDF) which were immortalized by the combination of human telomerase reverse transcriptase (hTERT) and SV40 early region (ER). These v-src-expressing HDF exhibit more drastic morphological changes, aggressive tumorigenecity in nude mice, and higher activity of both MAPK and PI3K signaling pathways when compared to the equivalent HDF transformed by H-ras V12. Curiously, there is no such difference between v-Src and H-ras V12 in the transformation of rodent fibroblasts. Such highly tumorigenic potential of v-Src is not limited to fibroblasts, and we have succeeded to transform normal human mammary epithelial cells (HMEC) into aggressive tumor cells by the similar procedure as in HDF. These v-Src transformed HMEC should provide a useful model cell system for understanding the molecular basis of some types of human breast cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):A44.
Abstract A45: The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation
Authors: Choi Hong Seok , Namgoog Gwang Mo , Cho Hae-Gook 
Published: May 2012

Abstract
Phosphorylation of proteins on serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis/trans isomerase Pin1 and is a central signaling mechanism in cell proliferation and transformation. Although Pin1 is frequently overexpressed in hepatocellular carcinoma (HCC), the molecular mechanism of Pin1 in HCC has not been completely elucidated. Here, we show that Pin1 interacts with p70S6K in vitro and ex vivo. Overexpression of Pin1 resulted in enhanced p70S6K phosphorylation induced by insulin in SK-HEP-1 cells. In contrast, Pin1−/− mouse embryonic fibroblasts (MEFs) exhibited significantly decreased insulin-induced p70S6K phosphorylation compared to Pin1+/+ MEFs. Furthermore, Pin1 enhanced the insulin-induced ERK1/2 phosphorylation through its interaction with p70S6K, whereas the inhibition of p70S6K activity by rapamycin suppressed insulin-induced ERK1/2 phosphorylation in SK-HEP-1 cells. Hence, Pin1 affected AP-1 activity through p70S6K-ERK1/2 signaling in SK-HEP-1 cells. Most importantly, Pin1-overexpressing JB6 Cl41 cells enhanced neoplastic cell transformation promoted by insulin much more than GFP-overexpressing JB6 Cl41 control cells. These results imply that Pin1 amplifies insulin signaling in hepatocarcinoma cells through its interaction with p70S6K, suggesting that Pin1 plays an important role in insulin-induced tumorigenesis and is a potential therapeutic target in hepatocarcinoma.
Citation Information: Cancer Res 2009;69(23 Suppl):A45.
Abstract A46: Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF
Authors: Cho Hae-Gook , Namgoog Gwang Mo , Choi Hong Seok 
Published: May 2012

Abstract
Tumor progression locus-2 (Tpl-2) kinase is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family that has been implicated in cellular transformation. The enhanced expression of this protein has been shown to activate both the MAPK and c-Jun N-terminal kinase (JNK) pathways. However the molecular mechanisms responsible for the oncogenic potential of Tpl-2 are still largely unknown. Here, we show that Tpl-2 interacts with p53 both in vitro and ex vivo. The overexpression of Tpl-2 inhibits the phosphorylation of p53 at serine 15 induced by EGF by upregulating the activity of protein phosphatase 2A (PP2A). In addition, the EGF-induced p53 activity was suppressed in the Tpl-2-wild-type-transfeted HEK 293 cells, but had no effect in the Tpl-2-mutant (S413A)-transfected cells. Furthermore, the Tpl-2 wild type, but not Tpl-2 mutant (S413A), showed increased EGF-induced c-fos promoter activity, followed by AP-1 transactivation activity, which is associated with the cell transformation prompted by the H-Ras-Tpl-2-AP-1 signaling axis. These results suggest that Tpl-2 plays an important role in EGF-induced carcinogenesis by inactivating the p53 tumor suppressor.
Citation Information: Cancer Res 2009;69(23 Suppl):A46.
Abstract A5: Transient TGFβ exposure reprograms mouse mammary epithelial cells in vitro and in vivo
Authors: Seo Jae-Hong , Dunphy Karen A. , Kim Daniel , Roberts Amy L. , Yan Haoheng , Tao Luwei , Hagen Mary J. , Jerry D. Joseph 
Published: May 2012

Abstract
Transforming growth factor beta (TGFβ) has been shown to inhibit growth of normal breast epithelium, but promotes aggressive behaviors in breast carcinomas. Normal breast epithelia are exposed transiently to increased levels of TGFβ during involution. During radiation therapy for breast cancer, the breast epithelium is also exposed transiently to TGFβ.While TGFβ restricts growth of most normal breast epithelia, it may have divergent effects on progenitor cells. The CDβgeo cells have been shown to be enriched for mammary progenitor cells (Deugnier et al., 2006). Treatment of CDβgeo cells with TGFβ1 resulted in modest decreases in E-cadherin levels after 14 days (TD0). However, withdrawal of TGFβ and passaging the cells over 14 days resulted in transdifferentiation (TD14). In contrast to the parental CDβgeo cells, the TD14 cells had decreased expression of E-cadherin (3-fold, p&lt;0.05) and increased levels of N-cadherin (4-fold, p&lt;0.05). The TD14 cells also exhibited a striking increasing in motility and invasion of Matrigel (invasion index=3.7-fold), but there was no difference in proliferation rates between the CDβgeo and TD14 cells. The TD14 also were strongly tumorigenic when transplanted into cleared mammary fat pads (TE50=43 days). To determine if Smad signaling is required, Smad4 expression was knocked down using shRNA (ΔSmad4). The ΔSmad4 cells exhibited decreased expression of E-cadherin, but were not tumorigenic when transplanted into cleared mammary fat pads. The levels of Snail mRNA in CDβgeo cells were increased 3-fold following exposure to TGFβ1 treatment (TD14 cells). Levels of Snail were also increased (3.5-fold) in tumors derived from the TD14 cells. Although E-cadherin expression was reduced in ΔSmad4 cells, the levels of Snail remained equivalent to that in CDβgeo cells even after exposure to TGFβ1. These results demonstrate that transient exposure to TGF-β1 acts through Smad4-dependent signals to cause irreversible changes in the expression of Snail resulting in tumorigenic phenotype.
Citation Information: Cancer Res 2009;69(23 Suppl):A5.