bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-119: A 3′UTR KRAS-variant and triple negative breast cancer
Authors: Paranjape Trupti , Weidhaas Joanne B. 
Published: June 2012

Abstract
Background: We previously identified a functional variant in a let-7 microRNA complementary site in the 3′UTR of the KRAS oncogene (rs61764370) associated with cancer. Here we investigate the association of this variant with breast cancer and breast cancer tumor biology.
Methods: We genotyped subjects from three breast cancer cohorts and controls (n=2323), and additionally evaluated the association of the KRAS-variant with genome wide mRNA and specific microRNA expression in triple negative breast cancer (TNBC) patients.
Findings: The KRAS-variant is significantly associated with ER/PR negative breast cancer risk in premenopausal women by case control analysis (p = 0.015). A breast cancer cohort with complete receptor status shows the association of the KRAS-variant specifically with TNBC (p = 0.044), and a case control analysis indicates a significant increased risk of TNBC in KRAS-variant positive premenopausal women (OR = 2.31, CI = 1.26–4.22, p&lt;0.007, n = 361). Gene expression analysis of TNBC tumors with and without the KRAS-variant indicates that KRAS-variant positive tumors have significantly altered gene expression, and are enriched for the luminal progenitor and BRCA1 deficiency signatures. MicroRNA analysis indicates lower levels of let-7 microRNA species.
Interpretation: These findings support the hypothesis that the KRAS-variant may be a genetic marker for the development of triple negative breast cancer in premenopausal women. Furthermore, tumors harboring the KRAS-variant appear to have altered gene and microRNA expression that can distinguish them from other triple negative breast cancers. Thus, the variant may help molecularly and biologically stratify patients with triple negative breast tumors.
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 LB-119. doi:10.1158/1538-7445.AM2011-LB-119
Abstract LB-120: Oncogenic property of FOXP1 isoform3 in diffuse large B-cell lymphoma.
Authors: Kim Saerom , Kim Soyeon , Kim Eunkyung , Kim Tae Min , Heo Dae Seog 
Published: June 2012

Abstract
Introduction. FOXP1 forkhead transcription factor is one of the markers of activated B-cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). High level expression of FOXP1 has been reported to have a poor prognosis and nine different truncated isoforms of N-terminally truncated FOXP1 were found apart from full length FOXP1. However, the biologic roles of isoforms are not fully investigated. In this study, oncogenic effect of FOXP1 smaller isoform3 (FOXP1.3) was evaluated and complementary regulation between FOXP1 and FOXP1.3 was investigated.
Methods. Various B-cell lymphoma cell lines (BJAB, OCI-Ly-19, SU-DHL-6, U2932, U2940 and Daudi) were used to evaluate FOXP1 isoforms by immunoblotting and RT-PCR. Two different cell lines, U2932 (ABC-DLBCL) and U2940 (primary mediastinal B-cell lymphoma) cells were exposed to FOXP1-specific siRNA and transfected with FOXP1.3 plasmid tagged with flag for up to 48 hr, respectively. After silencing and over-expression of FOXP1, cell proliferation was measured by colorimetric technique. Therapeutic effects were also confirmed by the treatment of monoclonal anti-CD20 antibody, rituximab at a dose of 10 μg/106 cells for 3 days.
Results. Differential patterns of expression of FOXP1 isoforms were detected in various DLBCL cell lines on both protein and mRNA levels. U2940 cells exhibited high level of endogenous FOXP1.3 compared with other cell lines. The suppression of FOXP1 by siRNA led to the over-expression of FOXP1.3 in DLBCL cell lines. Up-regulation of FOXP1.3 showed approx. 2.5 folds increase of cell proliferation by colorimetric assay. This was due to induction of survival pathways involving NF-κB and NFAT2 transcriptional factors, which are nuclear transcriptional factors that represent major neoplastic events in DLBCL. Activation of FOXP1.3 was also observed after exposure to rituximab. Rituximab suppressed FOXP1 and dramatically increased expression levels of FOXP1.3 simultaneously in a time-dependent manner.
Conclusion. A novel oncogenic property of FOXP1.3 and its complementary regulation with FOXP1 in DLBCL cell lines was observed. These data also suggest a possible mechanism of resistance to rituximab treatment.
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 LB-120. doi:10.1158/1538-7445.AM2011-LB-120
Abstract LB-121: Polymorphic variants in PPARGC1A and PCMTD1 associate with earlier age of onset in ER-negative breast cancer
Authors: Terlizzi Joseph P. , Vazquez Alexei , Mehta Madhura Sreenath , Hirshfield Kim 
Published: June 2012

Abstract
Background:
Breast cancer is the most frequent cancer and leading cause of cancer death among women worldwide. As &lt;10% of breast cancers are due to mutations in BRCA1 and BRCA2, other perturbations such as single nucleotide polymorphisms (SNPs) may be genetic contributors. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) enhances estrogen receptor (ER) and estrogen related receptor gamma (ERRγ) activity by acting as a coactivator. ERRγ has been demonstrated to regulate vascular endothelial growth factor mRNA expression in both ER-positive and ER-negative breast cancer cell lines, indicating that it may accelerate angiogenesis and metastasis. PCMTD1 encodes protein-L-isoaspartate O-methyltransferase domain-containing protein 1, a S-adenosylmethionine-dependent methyltransferase whose biological relevance is largely unknown to present. SNPs in PPARGC1A have been correlated with metabolic diseases, but within the three studies evaluating cancer phenotypes for this gene, only Thr612Met (76873 C→T) revealed a significant association with familial breast cancers.
Experimental Procedure:
SNPs in PPARGC1A and PCMTD1 were selected using a bioinformatics approach based on SNP associations with drug response in NCI-60 cell lines and evidence of selection bias for haplotype frequencies. Allelic discrimination assays were performed on genomic DNA isolated from whole blood from over 900 Caucasian breast cancer patients with ductal carcinomas. Clinical information was linked to genotypes to search for genotype-phenotype correlations, and statistical analyses were carried out.
Results:
Analysis of PPARGC1A rs4619879 revealed a mean age of diagnosis of ER-negative cases for CC and AA carriers at 50.1 and 43.8 years, respectively (p=0.019). The difference was less striking in ER-positive ductal carcinomas, with only a 2.7year earlier onset for AA carriers (p=0.013). For PCMTD1 rs9298462, the mean age at diagnosis of ER-negative cases for CC carriers was 41.2, compared to 48.8 for the TT carriers (p=0.004). No significant difference was seen in ER-positive ductal carcinomas (p=0.15).
Conclusions:
Our results indicate that polymorphisms in PPARGC1A and PCMTD1, two transcriptional regulators, may play a role in age at diagnosis in breast cancer, particularly ER-negative ductal carcinomas. We are performing functional studies to further evaluate these findings and to elucidate the molecular mechanisms underlying these observations.
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 LB-121. doi:10.1158/1538-7445.AM2011-LB-121
Abstract LB-126: Negative regulation of the Hippo pathway by the E3 ubiquitin ligase ITCH promotes tumorigenicity
Authors: Salah Zaidoun , Melino Gerry , Aqeilan Rami 
Published: June 2012

Abstract
The Hippo tumor suppressor pathway regulates cellular proliferation and survival, thus has profound effects on normal cell fate and tumorigenesis. WW domain-containing proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY) containing targets. Here, we showed that the E3 ligase ITCH regulates stability of LATS1, a key components of the Hippo pathway through protein-protein interaction of the PPxY motifs of LATS1 and the WW domains of ITCH by showing both endogenous and exogenous LATS1 and ITCH co-immunoprecipitation and that a double mutation in LATS1 PPxY motifs abrogates ITCH-LATS1 interaction. Wild type, but not mutant, ITCH catalyzed ubiquitination of LATS1 and stimulated its proteosomal degradation. Activation of the Hippo pathway, either by overexpressing MST2 or culturing cells at high density, induced ITCH and subsequent degradation of LATS1. Modulation of LATS1 levels via ITCH overexpression or Knockdown was associated with status of YAP phosphorylation, its subcellular localization and subsequently its transcription co-activation function. While ITCH knockdown induced epithelial-mesenchymal transition (EMT) phenotypes and tumorigenicity, ITCH overexpression induced these phenotypes. These findings provide evidence of a novel functional link between ITCH and Hippo pathway, underscoring a critical role for this association in tumorogenesis.
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 LB-126. doi:10.1158/1538-7445.AM2011-LB-126
Abstract LB-132: Protein interactome between PTEN and cancer-associated mutant demonstrated the regulatory pathway of migration through its novel interactors
Authors: Goh Mei Xian , Gunaratne Jayantha , Swa Lee Foon , Sanford Emma M. , Lee Fen Yee , Hogue Kelly A. , Blackstock Walter , Okumura Koichi 
Published: June 2012

Abstract
Mutation of the PTEN tumor suppressor protein frequently occurs in a variety of human cancers. PTEN is a phosphatase that negatively regulates the phosphatidyl-inositol-3-kinase (PI3K) pathway, and regulates cell proliferation, apoptosis, and cell motility. Though the tumor suppressive function involves PTEN's lipid phosphatase-dependent and -independent activities, the mechanism leading to the phosphatase-independent function of PTEN is poorly understood. Some PTEN mutants have lipid phosphatase activity but fail to suppress cell growth. Here we use a cancer associated mutant, G20E, to gain insight into the phosphatase-independent function of PTEN by investigating protein-protein interactions using mass spectrometry (MS)-based stable isotope labeling by amino acids in cell culture (SILAC). A strategy named parallel affinity purification (PAP) and SILAC has been developed to prioritize interactors and to compare the interactions between wild-type and G20E PTEN. Clustering of the prioritized interactors acquired by the PAP-SILAC approach are mainly involved in cell migration and apoptosis pathways, suggesting deregulation of the pathways could be involved in the tumorigenesis derived by the PTEN mutant. We further demonstrate that the one of wild-type specific interactor is required for the regulatory function of wild-type PTEN in cell migration. Furthermore, the other wild type specific interactor affects cell growth. These finding contribute to a better understanding of the mechanisms of PTEN's functions.
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 LB-132. doi:10.1158/1538-7445.AM2011-LB-132
Abstract LB-150: Influence of CD103-E-cadherin interaction in stimulatory versus cytotoxic immune synapse formed between CTL and specific tumor cell
Authors: Franciszkiewicz Katarzyna , Floc'h Audrey Le , Boutet Marie , Mami-Chouaib Fathia 
Published: June 2012

Abstract
We have previously reported that interaction of integrin αE(CD103)β7, often expressed by tumor-infiltrating lymphocytes (TIL), with E-cadherin on epithelial tumor cells is required for polarized exocytosis of cytotoxic granules resulting in target cell lysis. Our results also indicated that binding of CD103 on tumor-specific cytotoxic T lymphocytes (CTL) to a recombinant E-cadherin-Fc molecule is sufficient to induce polarization of cytolytic granules in a phospholipase Cγ-dependent pathway, whereas degranulation also requires co-engagement of the T-cell receptor (TCR). In the present study, we compared the ultrastructure of the immune synapses formed between CD103+ or CD103- CTL and specific lung cancer cells, and analyzed the involvement of adhesion/costimulatory molecules in the activation of cytotoxicity versus stimulatory functions. Our results indicated that stimulatory and lytic synapses display differential activation threshold and intercellular molecular requirements.
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 LB-150. doi:10.1158/1538-7445.AM2011-LB-150
Abstract LB-154: Anti-tumor effect of dendritic cell-based immunotherapy in the patients with advanced breast cancer.
Authors: Akiyama Shinichiro , Yasuda Hiroyasu , Abe Hiroyuki 
Published: June 2012

Abstract
Background and objective: Tumor-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by dendritic cell (DC)-based vaccination. However, clinical responses to the immunotherapy with DC vaccination have only been observed in a minority of patients with solid cancer. In the current study, the clinical efficacy of the DC vaccine pulsed with the peptide derived from breast cancer-associated antigens has been evaluated in the patients with advanced, inoperable breast cancer.
Patients and Methods: 21patients with advanced, inoperable breast cancer refractory to standard treatment were entered the study. DCs which were generated from CD14+ monocytes from leukapheresis by 6-day cultivation with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4, were matured by OK-432, a streptococcal agent, and were pulsed with the pancreatic cancer-associated antigens, such as WT1, MUC1. These DCs (1 × 107) were intradermally administered more than 5 times at 14-day intervals.
Results: Of the 21 patients, complete response (CR) was observed in 0 (0%), partial response (PR) in 2 (9.6%), stable disease (SD) in 7 (33.3%), progressive disease (PD) in 12 (57.1%). Response rate was 9.6%. Tumor control rate was 42.9%. Mean survival time after DC therapy was 514days. Severe side effects of more than grade 3 which were assessed in accordance with NCI-Common Toxicity Criteria v.2.0, were not observed.
Conclusions: It was strongly suggested that the DC vaccination pulsed with cancer associated-peptides was safety and effective in the patients with the inoperable breast cancer refractory to standard treatment.
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 LB-154. doi:10.1158/1538-7445.AM2011-LB-154
Abstract LB-227: New SRC inhibitors induce p27-mediated apoptosis in mesothelioma cell lines
Authors: Indovina Paola , Giorgi Francesca , Rizzo Valeria , Khadang Baharak , Schenone Silvia , Mattioli Eliseo , Tomei Valentina , Dimarzo Domenico , Forte Iris M. , D'Urso Vittorio , Botta Maurizio , Giordano Antonio , Pentimalli Francesca 
Published: June 2012

Abstract
Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no specific curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo-[3,4-d]-pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclin-dependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a well-established adverse prognostic factor in MM and p27 nuclear localization is crucial for its tumor suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy.
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 LB-227. doi:10.1158/1538-7445.AM2011-LB-227
Abstract LB-234: Aptamer-prodrugs for targeted cancer therapy
Authors: Levy Matthew 
Published: June 2012

Abstract
Many current cancer therapy drugs are severely hindered in efficiency due to issues of specificity and targeting. We aim to improve the efficacy of these drugs by linking or incorporating them directly to non-immunogenic targeting molecules called aptamers. These aptamers would guide drugs to tumor sites thereby limiting off-target effects and toxicity.
As initial targets, we have developed aptamer-prodrugs directed against the cancer markers prostate membrane specific antigen (PSMA) and human transferrin receptor (hTfR). These constructs are capable of binding and internalizing specifically into target cells, but not into non-target cells in tissue culture. We are currently testing the cancer-specific toxicity of several FDA-approved cancer drugs delivered to cells via these aptamers. Additionally, we are developing approaches to directly identify tumor homing RNAs. These molecules will similarly be adapted for drug delivery.
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 LB-234. doi:10.1158/1538-7445.AM2011-LB-234
Abstract LB-239: Genetic approaches for next generation of breast cancer tailored therapies
Authors: Silva Jose , Rodriguez Ruth 
Published: June 2012

Abstract
Cancer therapy has radically changed during the last decade. Novel therapies based on the specific molecular changes that drive tumorigenesis in every patient are emerging as low toxicity and more efficient alternatives to classical treatments. However, even these ideal tailored therapies fail to provide a long-term cure and can only delay the progression of the disease.
An alternative promising approach is the use of genetic synthetic lethal interactions. These occur when two genetic alterations that are individually innocuous appear in the same cell causing growth inhibition. This concept can be exploited to identify genes that, when inhibited, exclusively reduce the viability of tumor cells that carry a preexisting genetic lesion. Although synthetic lethality has always been proposed as an attractive anticancer approach with proven success, identification of these genetic interactions has remained elusive mainly because of the lack of proper genetic tools. However, RNA interference (RNAi) technology has emerged as a very powerful approach to attenuate the expression of any chosen gene. Thus, we envision using RNAi to identify genes that, when attenuated, exclusively reduce the viability of tumor cells carrying specific genetic lesions without affecting normal ones.
During the last years, we have pioneered the development of RNAi based genetic tools for studies in mammalian cells. Thus, we have generated a highly efficient RNAi library that allows us to block any gene of interest in the human genome. Additionally, we have developed a microarray-based analytical platform that, when combined with our RNAi library, greatly facilitates genome-wide RNAi studies. This technology represents a unique opportunity to identify synthetic lethal effects with major cancer alterations. In this project we have started to apply our state-of-the-art technology to uncover synthetic lethal interaction with the major breast cancer genes (ErbB2, c-Myc, Cyclin-D1 and RB).
These functional studies have already revealed that Stat-3 is synthetic lethal with activation of ErbB2. Thus, attenuating the activation levels of Stat-3 using small molecules inhibitors or RNAi silencing differentially reduced the viability of cells transformed with an ErbB2 oncogene. Mechanistically, we have linked this effect to the activation of an autocrine loop in which ErbB2 transformed cells secrete interleukin-6 (IL6) and upregulate its bona fide receptor IL6R. This activates the canonical JAK/STAT3 pathway increasing their tolerance to oncogene-induced stress.
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 LB-239. doi:10.1158/1538-7445.AM2011-LB-239