bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3888: Therapeutically activating the RB pathway in breast cancer: Key mechanisms of response and failure
Authors: Dean Jeffry L. , Reed Christopher A. , McClendon A. Kathleen , Knudsen Erik S. 
Published: February 2011

Abstract
A hallmark of cancer is the deregulation of cell cycle machinery, ultimately providing aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 plays a crucial role in the development of disease. Recently, a highly-specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast and additional cancers. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated in panel of breast cancer cell lines. These analyses demonstrated that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, thus, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies demonstrated a highly-specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F and the ability to attenuate CDK2 activity. In spite of these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3888.
Abstract 3889: Cyclin-dependent kinase 4 levels affect the number of hair follicle stem cells in mouse epidermis
Authors: Kim Sun Hye , Macías Everardo , Sistrunk Christopher , Rodriguez-Puebla Marcelo L. 
Published: February 2011

Abstract
The pRb/Cdk/cyclin/p16 pathway has been found altered in a majority of human neoplasias. In particular the Cyclin-dependent kinase 4 (CDK4) has been found mutated in familial melanoma, amplified or overexpressed in human gliomas, sporadic breast carcinomas and sarcomas. Additionally, a vast number of human cancers contain high levels of CDK4 activity due to loss of the Cdk inhibitor p16Ink4a or overexpression of its binding partner cyclin D1.
We have previously demonstrated that CDK4 ablation inhibits chemically-induced mouse skin papillomas, whereas forced expression of CDK4 in mouse epidermis (K5-CDK4) accelerates malignant progression to Squamous Cell Carcinomas (SCC). However, the mechanisms by which changes in CDK4 expression levels control skin tumorigenesis have not been established. In this model topical application of DMBA and TPA results in clonal expansion of a slow cycling stem cell population localized at the bulge area of the hair follicle. Thus, we hypothesize that CDK4 deletion or overexpression affects tumorigenesis by altering the characteristic and/or the number of Keratinocytes Stem Cells (KSC). To address this, we employed the K15-EGFP transgenic mouse model, which expresses EGFP under the control of the keratin 15 promoter in the bulge area of the hair follicle, to generated K15-EGFP/K5-CDK4as well as K15-EGFP/CDK4−/− compound mice.
Flow cytometry analysis of K15-EGFP/K5-CDK4 keratinocytes show 4-fold decrease in the number of KSC compared to K15-EGFP control mice. In contrast, K15-EGFP/CDK4−/− compound mice show 4-fold increase in the number of KSC compared with control siblings. Quantification of mRNA in the KSCs showed 3 to 5-fold increase in the CDK4 levels of KSC compared to non-Stem cell population, whereas mild or no changes in CDK2, Cyclin D1 and p27Kip1mRNA levels were detected.
Consistent with these data, we also determined an increase number of Labeled-Retaining Cells (LRC) in the hair follicle of CDK4−/− and decreased LRC in K5-CDK4 mice. Together these results are consistent with our hypothesis that changes in CDK4 expression affects the asymmetric cell division of KSC population favoring an increase in the transit amplifying (TA) cell pool and decrease of the KSC pool in K5-CDK4 and the opposite in CDK4−/− mice. As a result, this model predicts that the number of transit amplifying or progenitor cells correlate with the susceptibility to papilloma development.
Supported by NIH grant CA116328
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3889.
Abstract 39: Specific amino acid restriction affects glucose metabolism and induces oxidative damage of mitochondria in prostate cancer cells
Authors: Fu Ya-Min , Liu Xiaoyi , Meadows Gary G. 
Published: February 2011

Abstract
The purpose of this study was to examine how specific amino acid restriction targets mitochondria to induce apoptosis in DU145 and PC3 prostate cancer cells. This study shows that restriction of tyrosine and phenylalanine (Tyr/Phe), glutamine (Gln), and methionine (Met) differentially modulates glucose metabolism, the activity of pyruvate dehydrogenase (PDH) and antioxidant status in the mitochondria of these two cell lines. In DU145 cells, Gln and Met restriction but not Tyr/Phe restriction, increase glucose consumption and decrease lactate production. All the examined restrictions increase mitochondrial PDH activity and reactive oxygen species (ROS). Gln and Met restriction increase mitochondrial activity of glutathione peroxidase (GPx). Tyr/Phe and Met restriction increase mitochondrial activity of manganese superoxide dismutase (SOD) in the first 2 days of the restriction, and the activity returns to basal level on day 4 of restriction. Moreover, all the examined restrictions decrease reduced glutathione (GSH) and cause mitochondrial DNA damage. In PC3 cells, all of the examined restrictions reduce glucose consumption and lactate production; however, they do not alter mitochondrial PDH activity. Gln restriction increases accumulation of ROS and elevates mitochondrial GPx activity. Tyr/Phe restriction increases mitochondrial activity of SOD during the entire restriction period. Although all the restrictions decrease GSH in PC3 cells, they do not cause mitochondrial DNA damage. The data indicate that specific amino acid dependency differentially regulates glucose metabolism, oxidation-reduction reactions of mitochondria, and oxidative damage in mitochondria of these two cell lines. This partially explains how selective amino acid restriction targets mitochondria to induce apoptosis. (The project described was supported by Award Number R01CA101035 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 39.
Abstract 3900: Nuclear c-REL displaces p73 in partnering with DNp63 to suppress p21 expression and promote proliferation in head and neck cancer
Authors: Lu Hai , Duggal Praveen , Allen Clint , Yan Bin , Yang Xinping , Cohen Jonah , Nottingham Liesl , King Kathryn E. , Weinberg Wendy , Chen Zhong , Waes Carter Van 
Published: February 2011

Abstract
The tumor suppressor p53 is known as the ‘guardian of the genome’ owing to its ability to integrate many signals that control cell life or death. But the functions of the p53 tumor suppressor are commonly lost in cancer. The p53 family members p63 and p73 also contribute to tumor-suppressor function, because they share many common transcriptional targets with p53 and their activities contribute to the p53-dependent apoptosis and cell cycling of cancer cells. In p53 mutant tumors, TAp73 or TAp63 isoforms may compensate for p53 loss and respond to cell stress by upregulating genes involved in growth arrest and apoptosis. In contrast, DNp63 and DNp73 counteract the activities of TA isoforms, either by competing for common DNA binding elements or by blocking the TAp63 and TAp73 isoforms through direct protein-protein interactions. The mechanism regulating TA and DN crosstalk and balance remains uncertain. We recently reported that p53 and NF-KappaB family members DNp63 and c-Rel can interact to repress p21Cip1 and growth arrest in normal murine keratinocytes. Here we show that c-Rel, p63, and p73 exhibit aberrant expression and nuclear localization in a subset of head and neck squamous cell carcinoma (HNSCC). Co-immunoprecipitation, electromobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP) studies revealed that TNFalpha-induced or overexpressed nuclear c-Rel interact with DNp63, displace TAp73 from the nucleus, and from p63 promoter regulatory motifs of cell cycle and apoptotic genes p21, NOXA and PUMA. TNFalpha-induced or overexpressed c-Rel repressed, while c-Rel siRNA knockdown enhanced their expression and inhibited cell proliferation and survival. We conclude that aberrant and TNFalpha-mediated activation and interaction of c-Rel/DNp63 can displace TAp73 and block its key function in growth arrest and apoptosis. Our findings support a novel mechanism whereby an inflammatory cytokine, such as TNF-alpha, can promote c-Rel nuclear translocation, interaction with DNp63, and displacement of TAp73, to inhibit expression of key cell cycle inhibitor and apoptotic genes, which are downregulated in HNSCC and other cancers. This represents a novel form of cross-talk between NF-kappaB and TP53 family members and pathways that govern the switch between survival and death signals in HNSCC and other malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3900.
Abstract 3912: Comprehensive Characterization of SOX4 Protein Complexes in Prostate Cancer Cells
Authors: Lai Yu-Heng , Peng Junmin , Cheng Jessica , Moreno Carlos S. 
Published: February 2011

Abstract
Title: Comprehensive Characterization of SOX4 Protein Complexes in Prostate Cancer Cells.
Authors: Yu Heng Lai, Junmin Peng, Jessica Cheng, and Carlos S. Moreno
Abstract:
SOX4 is a developmental transcription factor in vertebrates that is required for differentiation and proliferation in multiple tissues. SOX4 is overexpressed in many human malignancies, but the precise role of SOX4 in cancer progression is still not well understood. Although it is known that SOX4 directly interacts with p53 and β-catenin, many of SOX4's protein binding partners remain unknown. Thus, the identification of additional SOX4 binding partners is essential for elucidating the mechanism of SOX4-mediated effects in cancer progression. We have adapted a one-step affinity purification method that allows rapid purification of via intracellular biotinylation of the amino-terminus of SOX4. We have transiently expressed SOX4 protein in LNCaP prostate cancer cells and purified SOX4 complexes with streptavidin-linked paramagnetic beads in order to perform large scale of proteomics analysis. We have identified several proteins that interact with SOX4 in vivo by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Details of these SOX4 protein-protein binding partners will be discussed. These proteomic data provide insights into the role of SOX4 in key pathways in cell proliferation, development, and cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3912.
Abstract 3914: Wilms Tumor-1 (WT-1) and its target genes in gliomagenesis
Authors: Chidambaram Archana , Dumur Catherine , Vanmeter Timothy E. , Fillmore Helen , Broaddus William C. 
Published: February 2011

Abstract
WT-1 - a zinc-finger transcription factor - plays an important role during development, and is associated with the development of tumors of varied origins. Our laboratory has previously demonstrated the expression and importance of WT-1 in the growth of glial neoplasms. In this study, we have sought to identify its downstream targets in the specific context of gliomas.
Methods & results: Using Real Time RT-PCR and Western Blotting, we demonstrate an inverse correlation between WT-1 and one of its established targets- IGF-1R. Also, using the gene expression profiling technique, we have identified some of its other target genes in U251-MG cells. Key genes that are down-regulated with WT-1 silencing include: PDGF-D, TYMS, INPP5A, EPAS-1 and CD97, while genes that are found to be up-regulated with WT-1 silencing include: TIMP-3 and LZTS-1. These results have been validated at the RNA and/ or protein level using Real Time RT-PCR and/ or Western Blot analysis. Further, we demonstrate the effects of manipulating WT-1 levels on some of these newly identified targets, selected for their importance in different aspects of tumor biology.
Conclusion: WT-1 is clearly implicated in the development and progression of gliomas. By identifying the molecular allies that help this protein promote oncogenesis, we hope to gain important insights for the development of a multi-molecular targeting strategy against these aggressive tumors
Abbreviations: IGF-1R: Insulin-like growth factor-1 Receptor; PDGF-D: Platelet-Derived Growth Factor-D; TYMS: Thymidylate Synthetase; INPP5A- Inositol Polyphosphate-5-Phosphatase; EPAS-1: endothelial PAS domain protein 1; TIMP-3: Tissue inhibitor metallopeptidase-3; LZTS-1: leucine zipper, putative tumor suppressor 1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3914.
Abstract 3922: Lef-1 is differentially expressed in endometrial cancer and appears to target cyclin D1 in endometrial tissue
Authors: Fornalik Hubert , Neff Traci , Park Soo , Shelton Dawne , Liu Xiaoming , Xie William , DeGeest Koen , Bender David , Buekers Thomas , Engelhardt John F. , Goodheart Michael J. 
Published: February 2011

Abstract
Objectives: The molecular pathways involving endometrial carcinogenesis and gland formation are currently unclear. We have previously reported on the involvement of Lymphoid Enhancing Factor-1 (Lef-1), a transcription factor, in the development and maintenance of glands within the mouse uterus. We have also demonstrated the overexpression of Lef-1 within human cancer samples. Cyclin D1, a downstream target of Lef-1, has been shown to be over-expressed in a myriad of human cancers. We hypothesize that Lef-1 is differentially expressed in human endometrial cancers and that cyclin D1 is regulated by Lef-1 in gland formation and cancer.
Methods: Using Lef-1 knock out (KO) mice and wild type (WT) controls we characterized the expression of cyclin D1 within the endometrial glands of the developing mouse endometrium. Using Western blot analysis and real time PCR, we also characterized and identified Lef-1 expression in different human endometrial cancer samples. Using both normal and cancerous human endometrial tissue samples, we immunostained for Lef-1 and cyclin D1 protein.
Results: Lef-1 expression is increased in certain subtypes of human endometrial cancer. In WT mice, cyclin D1 is localized to the developing gland bud by day 7, as compared to the KO mice, which express no cyclin D1 during this day. There appears to be cyclin D1 immunostaining within the same Lef-1 expressing cells within human endometrial cancers.
Conclusions: Lef-1 is overexpressed in specific subtypes of human endometrial cancer. Cyclin D1 appears to be present during endometrial gland formation within the mouse uterus and present within certain human endometrial cancer cells that express Lef-1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3922.
Abstract 3931: Elevated levels of poly(ADP-ribose) lead to enhanced efficacy of DNA-damaging chemotherapeutic agents
Authors: Zhou Yiran , Feng Xiaoxing , Koh David W. 
Published: February 2011

Abstract
The synthesis of poly(ADP-ribose) (PAR) is an immediate response to DNA damage. We reported previously that the failure to degrade PAR by inhibiting PAR glycohydrolase (PARG) leads to hypersensitivity to DNA damage. To investigate the ability of PARG inhibition to increase the effectiveness of DNA-damaging agents, we analyzed chromatin structure, DNA damage and repair, and cell death in PARG null trophoblast stem cells. PARG null cells displayed high levels of PAR-modified histones H1 and H2B, suggesting chromatin structural change. Chromatin decondensation was observed in PARG null cells by transmission electron microscopy. This structural change led to increased access of the DNA-modifying agent acridine orange and micrococcal nuclease. Analysis by Comet assay demonstrated an extraordinary amount of DNA damage induced by sublethal amounts of the DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine that was subsequently not repaired in PARG null cells. To determine if this chromatin decondensation might lead to enhanced access of DNA to currently utilized DNA-modifying chemotherapeutic agents, PARG null cells were treated with cisplatin and cyclophosphamide. Each induced 2 to 4 folds greater amounts of cell death in PARG null cells. Taken together, the results show that PARG inhibition enhances the efficacy of DNA-damaging agents by inducing a greater amount of DNA damage, a decrease in DNA repair, and an increase in cell death. The results therefore suggest that targeting PARG will enhance the effectiveness of DNA-modifying anti-cancer agents.
This research was supported by funding from the American Cancer Society and the Pharmaceutical Research Manufacturers of America.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3931.
Abstract 3932: Loss of PTEN sensitizes cells to DNA damaging agents in a RAD51-independent manner
Authors: Fraser Michael E. , Zhao Helen , Lundin Cecilia , Evans Andrew , Helleday Thomas , Bristow Robert G. 
Published: February 2011

Abstract
The PTEN tumor suppressor gene is frequently mutated or deleted in many cancers. While the role of PTEN as an inhibitor of the PI3K/Akt signaling pathway via its intrinsic lipid phosphatase activity has been well-studied, recent data suggest that loss of PTEN contributes to genomic instability through a PI3K/Akt-independent pathway via down-regulation of E2F1-dependent transactivation of Rad51, a key mediator of homologous recombination (HR). Cells with dysfunctional HR are sensitive to inhibitors of Poly(ADP)Ribose Polymerase (PARP) and therefore PTEN loss could sensitize cells to PARP inhibitors in a RAD51-dependent manner. Using PTEN-isogenic cell lines, cells treated with siRNA to PTEN and human prostate cancer cell lines with disparate PTEN status, we assessed whether PTEN loss is associated with altered expression of RAD51 protein. We also evaluated the effects of PTEN loss on sensitivity to PARP inhibition and various DNA damaging agents which sensitize cells based on deficiency in DNA double- and single-strand break repair, nucleotide excision repair and base excision repair (i.e. ionizing radiation (IR), camptothecin (CPT), Mitomycin C, cisplatin, ultraviolet radiation (UV), H2O2 and MMS). We observed that PTEN status did not predict RAD51 expression in PTEN−/− (PC3), PTEN+/− (DU145), and PTEN+/+ (22RV1) prostate cancer cells or xenografts in vitro or in vivo. Using a dedicated tissue microarray of localized prostate cancer, PTEN status (based on FISH) did not predict for RAD51 expression. Furthermore, we observed no difference in RAD51 mRNA or protein expression nor in E2F1 binding to the RAD51 promoter in PTEN-deficient HCT116 colorectal cancer cells or H1299 lung carcinoma cells treated with siRNA to PTEN. PTEN expression also did not alter RAD51 localization to IR-induced nuclear foci or UV microirradiation-induced DNA DSBs. However, using clonogenic assays, we observed that loss of PTEN did miminally sensitize cells to PARP inhibition with increased sensitization to MMC, cisplatin, UV, and IR. PTEN loss did not sensitize tumour cells to MMS, CPT or paclitaxel. Taken together, these data suggest that PTEN influences sensitivity to certain DNA damaging agents in a RAD51-independent manner. To understand this sensitivity, we are documenting gene expression changes in 200 DNA repair and replication genes using NanoString technology. A better understanding of the influence of PTEN on cellular sensitivity to chemo- and radiotherapy may ultimately help to guide treatment options for patients based on PTEN status (Sponsored by CCSRI, PCC and the Terry Fox Foundation).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3932.
Abstract 3933: Collagen-proteinase cross-talk promotes gemcitabine resistance in pancreatic cancer
Authors: Dangi-Garimella Surabhi Y. , Munshi Hidayatullah G. 
Published: February 2011

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival of ∼5%. A hallmark of PDAC is desmoplastic reaction (DR), the pronounced stromal reaction composed of extracellular matrix proteins along with activated fibroblasts, immune cells and endothelial cells. Although it has been suggested that the DR may be responsible for drug resistance, the mechanism is not well deciphered. We now show that collagen type I, the major component of DR, helps PDAC cells override the cell cycle checkpoint arrest induced by gemcitabine, the most commonly used chemotherapy for PDAC. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3D type I collagen gels demonstrated decreased activating phosphorylation of the checkpoint protein Chk1 following gemcitabine treatment. Interestingly, PDAC cells grown atop 3D collagen gels were more sensitive to gemcitabine treatment and demonstrated higher phospho-Chk1 levels compared to cells growing within 3D collagen gels, suggesting that collagen functions as a barrier to drug delivery. As we had previously shown that collagen could induce expression of the key collagenase membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14) by PDAC cells, we examined the contribution of MT1-MMP to drug resistance in our model system. Downregulating MT1-MMP with siRNA attenuated the effect of collagen on gemcitabine-induced checkpoint arrest. In contrast, MT1-MMP overexpression further protected the cells from gemcitabine-induced checkpoint arrest. Overall, our results demonstrate the complex interplay between the proteinase MT1-MMP and its substrate type I collagen in regulating chemotherapy resistance, and suggests that targeting MT1-MMP could help overcome PDAC drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3933.