bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2189: ΔN-ASPP2 is a novel isoform of the ASPP2 tumor suppressor and a regulator of ASPP2 function
Authors: Van Hook Kathryn , Wang Zhiping , Chen Dexi , Lee Hun Joo , Zhu Zhiyi , Lopez Charles 
Published: June 2012

Abstract
ASPP2 (Ankyrin-repeats, SH3 domain, Poly-proline domain-2) is a pro-apoptotic member of a family of p53 binding proteins that share homology in the C-terminus. ASPP2 expression is frequently suppressed in human cancers, and mouse models targeting the ASPP2 allele have shown that ASPP2 is a bonafide tumor suppressor. Although ASPP2 is a damage-inducible protein that stimulates apoptosis at least in part through a p53-mediated mechanism, ASPP2 also modulates p53-independent pathways to inhibit the tumorigenic phenotype. However, the complex mechanisms that control ASPP2 regulation and function remain unclear. Using 5’RACE and RT-PCR, we have discovered a new ASPP2 isoform (that we have named ΔN-ASPP2) that is generated from an internal transcription start site in mouse, rat, and human libraries. ΔN-ASPP2 is a predicted 880 amino acid protein that is missing the highly structured N-terminus important for apoptotic function. Western blotting with epitope specific antibodies, and immunoprecipitation followed by LC-MC, confirmed a 95 kD ASPP2 protein. Moreover as predicted, MEFs derived from our ASPP2+/- mouse targeted at exons 10-17, demonstrated decreased levels of ΔN-ASPP2 mRNA and 95 kD ASPP2 immunoreactive protein. Since the N-terminus of ASPP2 is important for pro-apoptotic and tumor suppressor function, we hypothesized that N-terminal truncated ΔN-ASPP2 could inhibit apoptosis and promote tumorigenesis. Indeed, overexpression of ΔN-ASPP2 inhibited UV-induced apoptosis, as well as promoted RasV12-induced 3T3 colony formation in cell culture. Interestingly, we found complex binding dynamics between ΔN-ASPP2, p53, and full-length ASPP2, suggesting that ΔN-ASPP2 could function as a dominant-negative. Importantly, and consistent with a role in promoting tumorigenesis, we found that ΔN-ASPP2 was highly overexpressed in a panel of 20 human breast tumor samples compared to matched adjacent normal tissue. In stark contrast, full-length ASPP2 expression was suppressed in these breast tumors. Together these data suggest that the novel ΔN-ASPP2 isoform may play a role in antagonizing ASPP2 and/or p53 function, and promoting resistance to therapy. These findings open new areas for investigation into a potential new target for therapy in human 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 2189. doi:10.1158/1538-7445.AM2011-2189
Abstract 2195: Scribble-mediated membrane targeting of PHLPP1 is required for its tumor suppressor function
Authors: Li Xin , Gao Tianyan 
Published: June 2012

Abstract
PHLPP1 is a Ser/Thr protein phosphatase that serves as a tumor suppressor by negatively regulating Akt. Here, we show that PHLPP1 is recruited to the basolateral membrane in colon cancer cells by binding to a scaffolding protein Scribble (Scrib). A small region in the C-terminus of PHLPP1 and the leucine-rich repeat (LRR) domain of Scrib are required for their interaction. Knockdown of Scrib results in a redistribution of PHLPP from the membrane to the cytoplasm, whereas overexpression of Scrib has the opposite effect. Furthermore, PHLPP1-dependent dephosphorylation of Akt is facilitated by the formation of Scrib, PHLPP1, and Akt trimeric complex in cells. IHC staining of human tissues reveals an identical localization pattern of PHLPP1 and Scrib in normal colonic epithelia, whereas downregulation or mislocalization of PHLPP1 and Scrib is observed in colorectal cancers. Taken together, our findings identify a functional interaction between PHLPP1 and Scrib in negatively regulating Akt signaling.
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 2195. doi:10.1158/1538-7445.AM2011-2195
Abstract 2197: Epithelial Mig-6 is critical for a tumor suppressor function in endometrial cancer
Authors: Kim Tae Hoon , Cho Sung Nam , Large Michael J. , Broaddus Russell R. , Orvis Grant D. , Behringer Richard R. , Jeong Jae-Wook 
Published: June 2012

Abstract
Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) action. A bias toward E2 action and away from P4 action underlies the tumorigenesis of endometrial adenocarcinoma which is the fourth most common cancer in women. In previous studies, we have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of PR (progesterone receptor) action in the uterus. Mig-6 is expressed in both the epithelium and stroma of the uterus. Conditional ablation of Mig-6 in all compartments of the uterus (PRcre/+ Mig-6f/f) results in infertility and leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. Our central hypothesis is that Mig-6 is a critical mediator of stromal-epithelial communication in pregnancy, steroid hormone regulation and tumor suppressor function. In order to understand the role of epithelial Mig-6 in the uterus, we generated a mouse model in which we specifically ablate epithelial endometrial Mig-6 using Wnt7a-cre mice (Wnt7acre+ Mig-6f/f). Wnt7acre+ Mig-6f/f mice are subfertile due to embryo abortion and display normal P4 attenuation of E2-mediated uterine hypertrophy. However, Wnt7acre+ Mig-6f/f mice develop endometrial hyperplasia at 5 months of age as well as estrogen-induced endometrial cancer. The expression of PR is reduced in Wnt7acre+ Mig-6f/f mice compared to control Mig-6f/f mice. Interestingly, the hyperplasia exhibited by the Wnt7acre+ Mig-6f/f mice is reversed by P4 treatment, contrary to what is observed in PRcre/+ Mig-6f/f mice. Also, the expression of ERα, as well as its target genes Muc-1, Clca3, Ltf and Birc1, is significantly decreased in the Wnt7acre+ Mig-6f/f mice as compared to the control and PRcre/+ Mig-6f/f after P4 treatment. Concurrently, stromal Mig-6 expression is significantly increased in Wnt7acre+ Mig-6f/f mice indicating that P4-induced stromal Mig-6 can reverse the hyperplasia seen in the Wnt7acre+ Mig-6f/f mice by regulating ERα expression level. These data suggest that epithelial Mig-6 plays an important tumor suppressor role during tumorigenesis in the uterus. (Supported by NIH, R01 HD057873)
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 2197. doi:10.1158/1538-7445.AM2011-2197
Abstract 22: Identifying chemotherapy resistance genes using outlier detection
Authors: De Ronde Jorma , Mulder Lennart , Lips Esther , Rodenhuis Sjoerd , Wessels Lodewyk 
Published: June 2012

Abstract
Motivation: Breast cancer is a heterogeneous disease and although gene expression analysis or immuno histo chemistry can be used to subclassify tumors into distinct subgroups, even within these subgroups there exist significant differences at the molecular level. When it comes to chemotherapy resistance, it appears highly unlikely that all resistant tumors share the same mechanism of action. Classical approaches have been unsuccessful in finding reliable biomarkers for therapy resistance and this may be due to the fact that these approaches are not sensitive to changes in small subgroups of samples.
Methods: Traditional analyses approaches, like a t-test or using the SAM approach, compare the two groups of samples for each gene, and identify genes with a significant difference in expression between the two groups. If only a small subset of the resistant tumors would show aberrant expression indicative of a resistance mechanism, then this would not be picked up by such approaches. Using a novel algorithm we try to circumvent this problem and specifically aim to find relatively small subgroups of tumors within the resistant group that show differential expression compared to the sensitive group.
Results: Using a positive control set, where we mixed in a small set of HER2-positive tumors in a larger HER2-negative set and by generating an artificial dataset we show that our algorithm is able to pick up all positive controls. These controls are not picked up by either a t-test or the SAM algorithm. Next, we applied the algorithm on a gene expression set of 195 patients that were neoadjuvantly treated and identified a number of genes that show an expression pattern that suggests a role in chemotherapy resistance in ER+ tumors. We validate our findings on a separate set of 90 patients.
Discussion: We have developed a novel algorithm that allows the identification of genes that show aberrant expression, relative to the reference group, in a small subset of the samples. Using this approach we identified a number of genes that are linked to chemotherapy resistance. The algorithm can be used in any type of analysis that involves the detection of small subsets of samples within one of the labeled classes, where the small subset shows behavior different from the average behavior of the remaining samples. Our approach can therefore be applied to a wide range of problems.
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 22. doi:10.1158/1538-7445.AM2011-22
Abstract 2210: Activation of PI3K in Merkel cell carcinoma
Authors: Nardi Valentina , Song Young Chul , Cosper Arjola K. , Lam Quynh , Barria Juan Antonio Santamaria , Boland Genevieve Marie , Yeap Beow , Bergethon Kristin , Scialabba Vanessa L. , Settleman Jeffrey , Ryan David P. , Borger Darrell R. , Hoang Mai P. , Bhan Atul K. , Iafrate Anthony J. , Cusack James C. , Engelman Jeffrey A. , Dias-Santagata Dora 
Published: June 2012

Abstract
Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, with a median survival time of 6.8 months for stage IV disease. Current chemotherapeutic regimens are largely ineffective. It is still unknown whether established oncogenes or tumor suppressors are major players in the pathogenesis of MCC. Recently, a new polyomavirus has been identified in 50 to 80% of MCC, but a mechanistic role for this virus in the pathogenesis of MCC has not yet been demonstrated. We hypothesized that deregulation of signaling pathways that are commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy.
Design: We retrospectively profiled 60 primary MCC samples diagnosed at the MGH from 1995 to 2010 using a recently developed SNaPshot genotyping assay to screen for the presence of common mutations in 13 cancer genes, many of which are targeted by FDA approved drugs or by targeted agents undergoing clinical trials. In addition, all MCC samples were tested for the presence of Merkel cell polyomavirus (MCPyV) using PCR.
Results: The SnaPshot assay identified mutations in 15% (9/60) of MCC primary tumors. The TP53 tumor suppressor gene was mutated in 3 of 60 cases and activating mutations in the p110 alpha subunit of the phosphatidylinositol 3-kinase (PIK3CA) gene were found in 6 of 60 cases. Sanger sequencing of the primary MCC tumors identified one additional PIK3CA mutation (R19K) that has not been previously described in cancer. In primary MCC cell lines, we observed that the presence of a PI3KCA activating mutation was associated with sensitivity to treatment with NVP-BEZ-235, a dual PI3K-mTOR inhibitor currently under active clinical development. Clinical correlations with PIK3CA mutational status and the presence of MCPyV are ongoing.
Conclusions: We discovered that a subset of patients with MCC (10%) carry activating mutations in PIK3CA. Furthermore, we found that a MCC cell line harboring a PIK3CA mutation is selectively sensitive to a PI3K inhibitor under clinical development. Our results suggest the relevance of screening patients with MCC for activation of the PI3K pathway, as these cancers may be particularly sensitive to PI3K pathway inhibitors.
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 2210. doi:10.1158/1538-7445.AM2011-2210
Abstract 2211: Quantitative analysis of IGF-1R expression and signaling pathway activation in FFPE xenograft and human tumor tissues
Authors: Thyparambil Sheeno , Hembrough Todd , Cao Liang , Krizman David , Darfler Marlene , Burrows Jon , Helman Lee 
Published: June 2012

Abstract
The IGF-1R signal pathway is activated in many cancer types which has led to active clinical development of both antibody and small molecule IGF1R targeted therapeutics. Multiple clinical trials targeting IGF1R are currently underway, however after initial optimism in NSCLC and Ewing's sarcoma, several trials have failed to show efficacy or had severe toxicity. Pretreatment quantitation of tumor IGF1R protein expression remains a challenge due to high homology between IGF1R and the insulin receptor. Thus, there is a need for a specific and quantitative clinical assay for IGF-1R protein expression. The ability to quantify IGF1R expression and determine signaling pathway activation status directly in formalin-fixed paraffin-embedded (FFPE) patient tissue biopsies should help identify and select patients most likely to benefit from anti-IGF1R therapies.
We have developed a quantitative IGF1R assay which can be performed directly in FFPE patient tissue. This approach is based on the Liquid Tissue®-SRM technology platform which enables relative and absolute quantification of proteins and their phosphorylation status directly in formalin fixed tissue.
The IGF1R- specific SRM assay was developed and preclinically validated on cell lines expressing a range of IGF1R protein. The final assay has a LOD of &lt;20 attomol/ug and an LOQ of ∼35 attomol/ug, values that are well in line with expected levels of expression in primary tumor sourced cell lines and xenograft explants. The expression levels of IGF1R in seven formalin fixed rhabdomyosarcoma (RMS) cell lines were measured by SRM mass spectrometry. We detected a range of IGF1R expression from 68 to 333 amol/ug for these cell lines, values that showed extremely high correlation with antibody based techniques (Cao et al, Cancer Res. 68:8039). We extended this quantitation study by measuring expression of IGF-1R in human rhabdomyosarcoma xenograft explants and a cohort of ∼40 embryonal and alveolar rhabdomyosarcoma tumors. Interestingly, in xenografts treated with a therapeutic IGF1R antibody, tumor regression was seen, and a loss of IGF1R expression was noted by SRM analysis. Our goal is to define expression levels of IGF1R in these tumors, and to validate this assay for use as a companion diagnostic in follow on clinical trials of IGF1R inhibitors.
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 2211. doi:10.1158/1538-7445.AM2011-2211
Abstract 2216: Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers
Authors: Yue Tingting , Maupin Kevin , Partyka Katie , Li Lin , Anderson Michelle A. , Brenner Dean , Simeone Diane , Feng Ziding , Brand Randall E. , Haab Brian B. 
Published: June 2012

Abstract
The CA 19-9 assay detects a carbohydrate antigen on multiple protein carriers, some of which may be preferential carriers of the antigen in cancer. We tested the hypothesis that the measurement of the CA 19-9 antigen on individual proteins could improve performance over the standard CA 19-9 assay. We used antibody arrays to measure the levels of the CA 19-9 antigen on multiple proteins in serum or plasma samples from patients with pancreatic adenocarcinoma or pancreatitis. Sample sets from three different institutions were examined, comprising 420 individual samples. The measurement of the CA 19-9 antigen on any individual protein did not improve upon the performance of the standard CA 19-9 assay (79-88% sensitivity at 75% specificity), owing to diversity among patients in their CA 19-9 protein carriers. However, a subset of cancer patients with no elevation in the standard CA 19-9 assay showed elevations of the CA 19-9 antigen specifically on the proteins MUC1, MUC5AC, or MUC16 in all three sample sets. By combining measurements of total CA 19-9 with CA 19-9 on these individual proteins, the sensitivity of cancer detection was raised to 85-100% in the three sample sets, at a specificity of 75%. This finding demonstrates the potential value of measuring glycans on specific proteins for improving biomarker performance. Furthermore, the definition of subgroups of patients based on the protein carriers of the CA 19-9 antigen and other glycans will guide the further development of informative biomarker panels. Diagnostic tests with improved sensitivity for detecting pancreatic cancer could have important applications for improving the treatment and management of patients suffering from this disease.
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 2216. doi:10.1158/1538-7445.AM2011-2216
Abstract 2230: Quantitative expression of the hedgehog (Hh) signaling pathway in gastric carcinoma: A novel protocol to process RNA from paraffin-embedded tissue
Authors: Akalu Abebe , Liebes Leonard , Xu Rulang , Schneider Robert , Takebe, Naoko , Cohen Deirdre 
Published: June 2012

Abstract
Background: The Hh pathway is an evolutionally highly conserved signaling cascade important in gastroesophageal embryonic pattern formation and stem cell response to tissue damage. Its aberrant activation has also been implicated in gastric cancer formation and progression. Multiple therapeutics targeting the Hh pathway have been developed and in order to test their activity and pharmacodynamic responses, routine and consistent gene expression measurement from clinical samples must be available.
Aims and Methods: The aim of this work was to measure levels of Hh pathway expression in both gastric tumors and normal gastric tissue, using a novel protocol of processing RNA from formalin fixed, paraffin-embedded tissue (FFPET). Total RNA was extracted from FFPET using a combination of Qiagen and RecoverAllTM kits according to the manufacturer's protocol(s). cDNA was synthesized using the iScriptTMcDNA Synthesis Kit and then a minimum of 20 ng RNA was pre-amplified using an Applied Biosystems pre-amplification cDNA kit. The primers for the Shh and Gli1genes were then added to the pre-amplification reaction and TaqManPreAmp master mix, amplified for 14 cycles on a thermal cycler and then real time PCR carried out for 40 cycles in duplicate. The relative quantification of the Shh and Gli1 genes were compared to the reference gene succinate dehydrogenase complex subunit A (SDHA) where the ratio for the change in expression for the selected gene = 2−ΔΔCT.
Results: The levels of gene expression in gastric adenocarcinomas for Shh and Gli1 were respectively 3.89 ± 0.49 (mean ± SEM, N = 11) and 4.57 ± 1.46. For 8 non-tumor gastric specimens, the CT values for Shh ranged from 30.24 to 35.81 and for Gli1 from 31.21 to 34.81 while for SDHA the mean CT was 18.4 ± 1.87. Based on these CT values, no expression of Shh and Gli1 was present in these non-tumor gastric tissues.
Conclusion: Hh pathway signaling can be quantitatively measured using as little as 20ng of RNA obtained from FFPET, making this methodology valuable in the clinic where tissue acquisition is often limited, as for gastric tumors. Using our methodology we found that there is increased Hh pathway expression in gastric carcinomas as compared to normal tissue, a finding consistent with previous reports in the literature. Supported by NO1-CM-07103-74 RECOVERY – ACTNOW Clinical Trial 8376 and NCI 2P30 CA16087-23, Tissue Acquisition and Banking Core.
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 2230. doi:10.1158/1538-7445.AM2011-2230
Abstract 2267: Long term prognostic impact of CD4 and CD8 lymphopenia and rapid recovery in a cohort of 220 patients with a 10 years follow-up
Authors: Peron Julien , Ray-Coquard Isabelle , Cassier Philippe , Labidi-Galy Intidhar , Tredan Olivier , Bachelor Thomas , Sebban Catherine , Biron Pierre , Glapisson Guillaume , Blay Jean-Yves 
Published: June 2012

Abstract
Introduction: Lymphopenia is frequently observed in patients with cancer and correlates with poor outcome in short term. We report here the long term 10 years prognosis value of the peripheral blood lymphocyte subsets and impact of lymphocyte variation during the first months of chemotherapy in a cohort of patients treated in 1999 and 2000 with a minimum 10 years follow-up.
Patients and methods: Peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD19, CD56) were quantified on Day 1, after 1 and 3 months of a treatment with chemotherapy using FACS in a prospective study of patients with cancer treated in a single oncology ward. Different tumors subtypes, stages and disease settings were included. Correlation of lymphocyte subset counts and variations with outcome was analyzed.
Results: Among the 220 included patients, 83 (38%) were treated for lymphoma, 15 (7%) for myeloma, 58 (26%) for sarcoma, 21 (9%) for breast cancer and 43 (19%) for other cancers. In univariate analysis baseline absolute lymphocyte count (ALC) &lt;700/μL, baseline CD4 count &lt; 450/μL and baseline CD8 &lt; 400/μL were found correlated to overall survival (OS) and progression free survival (PFS). In multivariate analysis, absolute lymphocyte count &lt;700/μL (HR 1.7, [95% CI, 1.1 – 2.4], p=0.008) and CD8 counts &lt;400/μL (HR 1.5, [95% CI, 1.1 – 2.1], p=0.019) were found to be independently correlated to overall survival. Among tumors curable with cytotoxic chemotherapy -lymphoma, germ cell cancer thymoma and localized carcinomas), no patients with ALC &lt;200/μL or baseline CD4 lymphocytes &lt;100/ μL had long term survival. Among patients with rarely curable tumors (metastatic carcinomas and sarcomas), patients with baseline ALC &lt;400/μL or baseline CD4 lymphocytes &lt;200/μL died within 18 months. We then investigated the impact of lymphocyte recovery during the first month and 3 months of chemotherapy. In lymphopenic patients (ALC &lt; 700/μL), recovery was not associated with an improved outcome. Conversely, lymphocyte increase between M0 and M1 was associated with a decreased OS (HR: 1.95 CI95% 1.17-3.26, p=0.009) in patients with ALC≥700/μl, in univariate and multivariate analysis.
Conclusion: A low absolute lymphocyte count and CD4 or CD8 lymphocyte count is major prognostic factor for overall survival in patients receiving chemotherapy. Early lymphocyte recovery is not associated with improved outcome in these patients.
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 2267. doi:10.1158/1538-7445.AM2011-2267