bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3132: C6orf69 is down-modulated by protein kinase C epsilon and exhibits increased expression in breast cancers
Authors: Garczarczyk Dorota , Hinger Doris , Gruber Peter , Hofmann Johann 
Published: June 2012

Abstract
Protein kinase C (PKC) comprises a serine/threonine kinase family of at least ten related isozymes. Protein kinase C epsilon (PKCε) has been shown previously to act as an oncogene, contributing to malignancy by tumor cell invasion, metastasis and inhibiting cell death. However, the precise function is not known at present. We investigated whether PKCε expression leads to alterations in the expression of other genes.
We found by gene array after overexpression of constitutively active PKCε that EST AA167550, of which 348 bases were known, was down-modulated. We obtained the full-length sequence of AA167550. It was identified as chromosome 6 open reading frame 69 gene (C6orf69). At least two distinct mRNAs were found to be transcribed from this gene. We generated an antibody and as shown by Western blotting, two proteins (47 and 40 kDa) were detected. The full length sequence of C6orf69 contains a BTB-BACK-Kelch domain usually involved in protein-protein interactions and implicated in the stability of actin filaments. C6orf69 co-immunoprecipitated with PKCε and bound to actin. PKCε/C6orf69 interaction was additionally confirmed by a yeast two-hybrid screen using C6orf69 full length as bait.
C6orf69 is expressed in many tissues except in heart, ovary, small intestine and leukocytes. In nine out of nine breast cancers, the expression levels were higher than in matched normal mammary tissue. C6orf69 contains four putative PKC phosphorylation sites. The C6orf69 protein is phosphorylated but is not a direct substrate of PKC isozymes, as demonstrated by in vitro PKC assays. Recently, BTB-domain containing proteins have been reported to regulate protein stability by recruiting proteins to the Cullin3 (Cul3) ubiquitin ligase leading to their degradation via ubiquitin/proteasome. By a yeast two-hybrid screen and co-immunoprecipitation we could demonstrate that C6orf69 is interacting specifically with Cul3. In addition, an in vivo ubiquitylation assay showed that overexpressed C6orf69 protein is efficiently polyubiquitylated, indicating to be a substrate of E3 ligase itself.
In summary, C6orf6 is down-modulated by PKCε, shows elevated expression in breast cancers compared to corresponding normal breast tissue, contains a BTB domain, interacts with PKCε, actin and Cul3. C6orf69 is phosporylated but not substrate of PKC isozymes and it is ubiquitylated.
This work was supported by grants P15039 and P19878 from the Austrian Science Fund (FWF).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3132. doi:10.1158/1538-7445.AM2011-3132
Abstract 3140: Analysis of candidate phosphatidylinositol 3’ kinase inhibitor biomarkers in matched synchronous primary and metastatic breast cancer tumors
Authors: Boyd Zachary S. , O'Brien Carol , Spoerke Jill , Mohan Sankar , Pandita Ajay , Fridlyand Jane , Punnoose Elizabeth , Koeppen Hartmut , Friedman Lori , Amler Lukas , Hampton Garret , Lackner Mark 
Published: June 2012

Abstract
The class I phosphatidylinositol 3’kinase (PI3K) is activated in a wide variety of human malignancies and inhibitors targeting the PI3K pathway hold great promise in the treatment and management of cancer. Successful development of such inhibitors will be enhanced by identification of responsive patients through the use of predictive biomarkers. Using cell lines and xenograft tumor models to evaluate a collection of putative biomarkers predictive of response to the selective inhibitor GDC-0941 in breast cancer, we have found excellent activity of the PI3K inhibitor GDC-0941 in luminal and HER2 amplified models, and that PIK3CA mutations and HER2 amplification are highly specific biomarkers of response to this agent. PTEN was predictive in some but not all cases, suggesting a need for further biomarkers of response in PTEN-driven disease. Here we report expanded analysis of human breast tumor samples, including matched primary tumor and lymph node metastases from 59 patients, suggesting primary and metastatic sites were generally concordant in terms of status of key biomarkers such as PTEN and PIK3CA, though several notable exceptions were discovered. We also compared PTEN status determined by immunohistochemistry (IHC) with a chromosomal fluorescence in situ hybridization (FISH) assay in a subset of tumors and found evidence for chromosomal deletion of the PTEN locus in several ER+ breast cancers, suggesting that some but not all of the PTEN loss observed in breast occurs at the chromosomal level and that both FISH and IHC may have utility as diagnostic assays. While we report that PIK3CA mutations and PTEN loss have reasonable prevalence to be considered as biomarkers for GDC-0941 in ER+ breast cancer, we have found a number of breast cancer models with no apparent pathway alterations but sensitivity to GDC-0941, indicating the need for additional predictive biomarkers. We identified a collection of genes for which expression levels indicate PI3K pathway activation and correlate with in vitro sensitivity to GDC-0941 as well as apparent prognostic significance in retrospective analysis of breast tumors. We report here expression analysis of these genes across matched primary breast tumors and lymph node metastases. In summary, our data provide strong rationale for developing a selective PI3K inhibitor in the ER+ breast cancer setting, and a framework for clinical implementation of predictive biomarker assays with potential utility in patient selection.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3140. doi:10.1158/1538-7445.AM2011-3140
Abstract 3148: Immunohistochemical analysis of HB-EGF expression in breast, colon, gastric, hepatocellular, lung, ovarian, pancreatic and prostate cancer
Authors: Halim Abdel-baset , Dauffenbach Lisa M. , Kerfoot Christopher A. , Stull William R. , Zwick-Wallasch Esther , Scheyer Richard , Senaldi Giorgio 
Published: June 2012

Abstract
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the epidermal growth factor (EGF) family of proteins. It is synthesized as a transmembrane protein, which can be cleaved at the cell surface to release the soluble ectodomain sHB-EGF. HB-EGF has been implicated in several physiological and pathological processes, including tumorigenesis and metastasis. Anti-HB-EGF therapeutic monoclonal antibodies are currently under investigation and hold promise for treating multiple types of cancer. In order to investigate the relationship between HB-EGF expression in cancer and response to therapy, an immunohistochemical assay to HB-EGF was developed and validated. Antigen retrieval and antibody titration studies were performed for six antibodies in order to select an antibody with proper performance characteristics. The antibodies were tested in characterized xenografts, characterized cell lines, placenta (HB-EGF-positive) and/or ovarian cancer. Of the antibodies tested, the AF-259-NA goat polyclonal antibody demonstrated the appropriate staining pattern in xenografts, cell lines and placenta. The optimized immunohistochemistry assay was used to stain cancer samples, and the frequency of moderate (2+) or strong (3+) staining in cancer cells was as follows: gastric = 50%, hepatocellular = 50%, lung = 40%; ovarian = 38%, colon = 37%, breast-ER+ = 20%, bladder = 10%; breast-HER2+ = 10%, pancreatic = 10%, breast-triple negative = 0%, prostate = 0%. When compared by average H-score, the cancer ranked in the following order (H-score in parenthesis): Hepatocellular (69), ovarian (37), gastric (23), breast-HER2+ (14), breast-ER+ (12), pancreatic (10), lung (5), breast-triple negative (2), colon (2), bladder (1), prostate (1). For comparison, H-scores for normal tissues were as follows: Normal bladder epithelium (74), stomach (24), colon (8), prostate (3), ovary (1), liver (1), breast (0), lung (0) and epidermis (0). In summary, immunohistochemistry using the AF-259-NA antibody produces the expected staining pattern in characterized samples and can be applied to human cancer samples to evaluate the relationship between clinical response and HB-EGF expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3148. doi:10.1158/1538-7445.AM2011-3148
Abstract 3149: OncoPredictor: A systematic approach for predicting responsive cancer populations from large scale cell line screening
Authors: Tomilo Mark , Eddy Sean F. , Banka Wendy Lockwood , Sadis Seth E. , Williams Paul D. , Wyngaard Peter J. , O'Day Christine , Ovechkino Yulia , Warrior Usha , Rhodes Daniel R. 
Published: June 2012

Abstract
Investigational new drugs for cancer must demonstrate convincing preclinical efficacy and a compelling strategy to translate preclinical observations to the clinical setting. Personalized medicine approaches are gaining wider acceptance, and large scale cell line databases have demonstrated utility in identifying biomarkers of drug response that can inform clinical development strategies. However, the lack of an integrated platform to translate preclinical biomarker profiles to clinical populations limits the power of this approach. To solve this problem we developed, first, a cell line screening and genomic analysis pipeline that associates drug response across 200+ cell lines with mutation, DNA copy number, and gene expression biomarkers; and second, a parallel database of biomarker frequencies in clinical tumor samples, compiled from all available published genomic data. In the present study, we tested 8 targeted anti-cancer agents and identified cell line biomarkers representing each of the genomic data types – mutation, DNA amplification, and gene over-expression – and then assessed the distribution of these biomarkers across tumor samples. In each case the tumor populations predicted to be responsive by this unsupervised approach were validated by results from clinical trials. We also present an example of biomarker results leading to potential new indications for an approved drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3149. doi:10.1158/1538-7445.AM2011-3149
Abstract 3150: Epithelial mesenchymal transition (EMT) and IGF-2 expression as determinants of sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma
Authors: Zhao Hui , Desai Vidhi , Wang Jian , Epstein David , Miglarese Mark , Rizzo Elizabeth 
Published: June 2012

Abstract
Hepatocellular carcinoma (HCC) affects over 600,000 patients worldwide and is the third leading cause of cancer-related death. Understanding signaling pathways that may be targeted for the treatment of HCC has been a major goal. A growing body of data indicates that inhibiting the type 1 insulin-like growth factor receptor (IGF-1R) might be an especially effective treatment strategy for HCC. Increased expression of IGF-2 as well as phospho-IGF-1R is observed in a subset of HCC tumors, and blockade of IGF-1R results in inhibition of proliferation for preclinical HCC cell models.
OSI-906 is a small molecule dual IGF-1R/IR inhibitor currently in advanced clinical development. In this report we sought to determine the effect of OSI-906 on proliferation for a panel of 21 HCC tumor cell lines as well as to investigate molecular determinants of responsiveness to OSI-906. A subset of HCC tumor cell lines was sensitive to OSI-906 in proliferation assays. Sensitivity to OSI-906 correlated with epithelial-mesenchymal-transition (EMT) status where the majority of epithelial HCC cell lines, but none of mesenchymal cell lines, were sensitive to OSI-906. We also found differential expression of IGF axis components, including IGF-2, in epithelial and mesenchymal tumor cell lines, which correlated with sensitivity to OSI-906. Induction of EMT upon treatment with TGFβ reduced sensitivity to OSI-906. Within a human HCC tumor database, epithelial tumors were identified to be enriched in one subgroup with higher IGF2 expression.
We have previously shown that both IGF-1R and IR can maintain tumor growth in a mouse mammary tumor model, and co-inhibition of both receptors is required for maximal inhibition of tumor growth. Herein, we find that OSI-906 sensitive HCC tumor cell lines expressed both phosphorylated IGF-1R and IR, and dual targeting of both receptors appears to be important for maximal inhibition of proliferation. Treatment of HuH-7 tumor cells with an IGF-1R neutralizing antibody was associated with increased IR signaling. In contrast OSI-906 fully inhibited both phosphorylated IR and IGF-1R and achieved greater inhibition of the IRS-AKT pathway compared to the IGF-1R antibody. Collectively, these data support the concept for dual IGF-1R/IR targeting HCC, where EMT status and expression of IGF-2 could be utilized to identify those patients most likely to benefit from treatment. A phase 2 clinical study evaluating OSI-906 in HCC is currently ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3150. doi:10.1158/1538-7445.AM2011-3150
Abstract 316: Keap1 and Nrf2 genetic mutations and polymorphisms: Associations with clinical outcome in endometrial cancer
Authors: Wong Tze Fang , Yoshinaga Kousuke , Monma Yasutake , Ito Kiyoshi , Niikura Hitoshi , Nagase Satoru , Yamamoto Masayuki , Yaegashi Nobuo 
Published: June 2012

Abstract
Background: Constitutive activation and increased expression of Nrf2 as a result of oncogenic mutations or other endogenous factors that cause derepression of Nrf2 by its cytosolic inhibitor, Keap1, contribute to tumor resistance to adjuvant treatment. As endometrial cancer generally has a lower response rate to adjuvant treatment, Keap1 and Nrf2 genes were sequenced to investigate their roles in endometrial cancer.
Materials and Methods: Tumor specimens from 105 individuals with endometrioid endometrial adenocarcinoma (Type I endometrial cancer) were sequenced. The specimens comprised 44 well-differentiated (FIGO grade 1), 38 moderately differentiated (FIGO grade 2) and 23 poorly differentiated (FIGO grade 3) tumors. Statistical analyses using the Fisher's exact test, Pearson's Chi-square test and Cox proportional hazards model were used to investigate the association of genetic mutations and haplotypes with patients’ annotated clinicopathologic characteristics.
Results: A total of ten novel Keap1 mutations were found in nine individuals, and two novel Nrf2 mutations were found in three individuals. One patient had two simultaneous Keap1 mutations, whereas two patients had the same type of Nrf2 genetic mutation. Two single nucleotide polymorphisms, rs1048290 and rs11545829 were found in high frequency in the present cohort. The non-synonymous genetic mutations and rs11545829 were not associated with patients’ clinicopathologic characteristics. In the adjuvant treatment subgroup, the rs1048290 c.1413C/G genotype was significantly associated with a better progression-free survival (hazard ratio, 0.25; 95% confidence interval [CI], 0.068 to 0.94; P=0.041). On multivariate analysis, rs1048290 was an independent prognostic factor for progression-free survival (hazard ratio, 0.16; 95% CI, 0.036 to 0.69; P=0.014).
Conclusion: Keap1 single nucleotide polymorphism rs1048290 may be a potential biomarker that enables individualized therapy using cytotoxic adjuvant treatment in endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2011-316
Abstract 3163: Tissue-micro array based IHC analysis of mTOR activity in DLBCL
Authors: Sticz Tamas B. , Mark Agnes , Hajdu Melinda , Timar Botond , Nemes Karolina , Kopper Laszlo , Sebestyen Anna 
Published: June 2012

Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases with several subtypes with differing responses to therapy. The standard initial therapy for DLBCL continues using regimens like R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), regardless of the subtypes. Targeted therapy offers a new approach to improve clinical responses. mTOR signaling has been shown to be activated in several lymphomas. mTOR inhibitors are being developed and are in clinical use in mantle cell lymphoma (MCL) therapy and clinical trials are ongoing in other high grade lymphomas as well. However, there is limited data about mTOR activity in different DLBCLs.
We evaluated immunohistochemical (IHC) results in biopsy materials from 79 DLBCL patients (42 females and 37 males, mean age 61 years), who were conventionally treated with R-CHOP, R-CEOP or CHOP therapy. Several antibodies (phospho-S6, phospho-p70S6K, phospho-mTOR, p-4EBP1, Mum1, CD10, bcl-6, bcl-2) were used and more than 700 IHC stainings were evaluated on TMA slides.
Mum1, CD10 and bcl-6 staining helped to distinguish between germinal center (GC) and non-germinal center B-cell derived DLBCL cases. Approximately 30% of cases were characterized as GC-derived DLBCL, which showed virtually no mTOR activity, as determined by phosphorylated S6 (p-S6) expression, the most sensitive marker (only weak p-S6 expression was detected in 2 cases). However, in about 80% of non-GC lymphoma cases, p-S6, p-mTOR, p-p70S6K and p-4EBP1 positivity was observed, which alludes to mTOR activity. Although the importance of mTOR activity is well demonstrated by mTOR mediated cyclinD1 expression in MCL, no statistical correlation was found between mTOR activity and the expression of pro-proliferative or anti-apoptotic factors (such as bcl-2 and bcl-6) in the examined DLBCL cases.
These results suggest that mTOR activity is characteristic in most non-GC derived DLBCLs. Similarly to MCL patients, those patients with poor survival may benefit from rapamycin derivatives or other treatments targeting mTOR. These rapalogs or other novel anti-mTOR agents may be used in addition to the regular R-CHOP therapy, however, patient selection criteria should be carefully considered.
Supported by OTKA-K68341 and OTKA-K81624 Projects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3163. doi:10.1158/1538-7445.AM2011-3163
Abstract 3164: Decreased expression of GDP-mannose-4,6-dehydratase (GMD) and GDP-fucose transporter is associated with squamous histology in non-small cell lung cancers (NSCLCs)
Authors: Honma Rio , Kinoshita Ichiro , Miyoshi Eiji , Matsuno Yoshihiro , Shimizu Yasushi , Kaga Kichizo , Taniguchi Naoyuki , Dosaka-Akita Hirotoshi 
Published: June 2012

Abstract
We have previously reported that low expression of α1,6-fucosyltransferase (FT), an enzyme for the core fucosylation of N-glycans, is significantly more prevalent in squamous cell carcinomas compared with non-squamous cell carcinomas of the lung. GMD generates GDP-fucose from GDP-mannose, and is imperative for the synthesis of all fucosylated oligosaccharides. GDP-fucose is transported into the Golgi apparatus by GDP-fucose transporter to serve as a substrate of FTs.
In the present study, we examined expression of GMD and GDP-fucose transporter by immunohistochemistry in 156 surgically resected NSCLCs. High, moderate and low expression of GMD was found in 32 (20.5%), 32 (20.5%) and 92 (59.0%) NSCLCs, respectively. High/moderate, low and no expression of GDP-fucose transporter was found in 7 (4.5%), 23 (14.7%) and 126 (80.8%) NSCLCs, respectively. Low GMD expression was significantly more prevalent in tumors from men than in those from women (p = 0.02), in tumors from smokers compared with nonsmokers (p = 0.047), and in squamous cell carcinomas compared with non-squamous cell carcinomas (p = 0.0003) by the χ2 test. Multivariate logistic regression analysis for the correlation between GMD expression and various characteristics revealed a significant association between low GMD expression and squamous cell carcinomas, as compared with non-squamous cell carcinomas (low vs. moderate, p = 0.005; low vs. high, p = 0.02). Among biological characteristics of tumors studied previously in this cohort of NSCLCs, Ki-67 labeling index was significantly higher in tumors with low GMD expression than in those with high GMD expression (low vs. high, p = 0.003). Low expression of α1,6-FT was more prevalent in tumors with low GMD expression than in those with moderate or high GMD expression (p = 0.002). Low GDP-fucose transporter expression was significantly more prevalent in squamous cell carcinomas compared with non-squamous cell carcinomas (p = 0.003) by the χ2 test. GMD and GDP-fucose transporter expressions were not associated with survival. These results indicate that GMD and GDP-fucose transporter may be new markers of NSCLCs with specificity for histology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3164. doi:10.1158/1538-7445.AM2011-3164