bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2320: In vivo characterization of small molecule inhibitors of replication protein A: Implications for cancer therapy
Authors: Neher Tracy M. , Bodenmiller Diane M. , Turchi John J. , Jalal Shadia I. 
Published: June 2012

Abstract
The nucleotide excision repair (NER) pathway catalyzes the removal of bulky DNA adducts from the genome and aids in maintaining genomic stability. The NER pathway has two subsets; global-genomic NER (GG-NER) and transcription coupled NER (TC-NER). They differ mainly in steps involving the recognition of the DNA lesion. The NER pathway plays a very important role in the recognition, removal and repair of intra-strand adducts induced by cisplatin; a commonly used chemotherapeutic agent. Previous studies have demonstrated that a decrease in NER activity enhances cancer sensitivity to cisplatin. The recognition of DNA damage involves a series of proteins including the xeroderma pigmentosum group A and C proteins (XPA and XPC) and Replication Protein A (RPA). RPA, a single-strand DNA binding protein, plays an essential role in both NER sub-pathways in addition to DNA replication. This makes RPA an ideal protein to target cancer therapy. Previous studies from our lab identified compounds which disrupt RPA's ssDNA binding activity in vitro. We sought to further characterize these RPA small molecule inhibitors (SMI) in cancer cell culture models. Using lung and ovarian cancer cell lines, viability curves, apoptosis assays, cell cycle analysis, signaling and transcription regulation were analyzed with single agent treatment and in combination with cisplatin. Results demonstrate potent cell killing in single agent studies and lengthening of the G1/ S-phase of the cell cycle. RPA SMIs also induce cell death through a classical apoptotic pathway. Additionally, data demonstrate a synergistic relationship with cisplatin with sequential treatment. Cell signaling analyses and DNA repair gene expression studies are ongoing to further determine the DNA damage response induced by these compounds. Overall these data demonstrate the therapeutic potential of SMI of RPA in treatment of cancer as single agents and in combination with cisplatin.
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 2320. doi:10.1158/1538-7445.AM2011-2320
Abstract 2327: Structural and kinetic characterization of crizotinib with wild-type and mutant anaplastic lymphoma kinase
Authors: McTigue Michele A. , Timofeevski Sergei L. , Liu Wei , Deng Ya-Li , Marrone Tami , Cui Jean , Brooun Alexei 
Published: June 2012

Abstract
Dysregulation of Anaplastic Lymphoma Kinase (ALK), primarily through gene translocations, has been shown to be involved in a variety of cancers. Crizotinib, an orally available small molecule inhibitor of the ALK tyrosine kinase has demonstrated marked efficacy in clinical trials of NSCLC patients harboring the EML4-ALK oncogenic gene rearrangement. Mutation of some residues within the ALK kinase domain have been reported to confer acquired or de novo resistance to crizotinib. To understand the binding of crizotinib to ALK and the mechanism of resistance of specific mutations we generated and kinetically characterized wild-type (WT) and mutant ALK kinase domains (KD). Additionally, ALK KD crystal structures were determined of the WT nonphosphorylated apoenzyme and complexes with crizotinib bound to WT and a L1196M gatekeeper mutation. No large protein conformational changes are necessary for crizotinib to bind to unliganded ALK. The interactions which crizotinib makes with ALK are similar to its binding to c-Met with the exception of notable differences in the position of the activation loop between ALK and c-Met. Mutation of the L1196 gatekeeper residue to methionine results in a ∼8-fold increase in catalytic efficiency of phosphorylation of an activation loop peptide and also more rapid enzyme auto-phosphorylation. In addition, inhibition of L1196M ALK by crizotinib was reduced ∼9-fold, compared to wild-type enzyme, from Ki determinations. The crystal structures show that L1196 or M1196 make direct contact with crizotinib. The diminished activity of crizotinib against L1196M ALK is therefore likely due to both higher intrinsic kinase activity and a subtle change in the ALK-crizotinib binding interactions.
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 2327. doi:10.1158/1538-7445.AM2011-2327
Abstract 233: Crosstalk of Her2 signaling and cell cycle control in the response to targeted therapeutics in breast cancer
Authors: Rivadeneira Dayana , Mercier Isabelle , Lisanti Michael P. , Witkiewicz Agnieska , Knudsen Erik S. 
Published: June 2012

Abstract
Previous studies have shown that breast cancer is associated with genetic and molecular modifications, such as aberrant amplification of oncogenes and/or inactivation of tumor suppressors. This heterogeneity translates into a wide range of breast cancer subtypes that exhibit different disease behaviors and therapeutic sensitivity. A common oncogenic activation used to classify subtypes of breast cancer is the overexpression of human epidermal growth factor receptor 2 (Her2). These highly aggressive tumors present distinct characteristics in disease progression and therapeutic response. One of the main complications with current therapies is therapeutic bypass and disease recurrence. Therefore, a better understanding of the mechanisms of therapy resistance and the development of alternative downstream interventions is of utmost significance.
There are several signaling cascades involved in tumor development that can be activated by the Her2 receptor tyrosine kinases. These signals ultimately converge on the cell cycle machinery, leading to the functional inactivation of RB to promote aberrant cell cycle progression and cell growth. In this context, RB pathway inactivation has been associated with aggressive tumor behavior and poor prognosis in breast cancer. In the current study, we explore the impact of RB inactivation in Her2 overexpressing disease in the response to Her2/EGFR antagonists. Furthermore, we assess the efficacy of reactivating the RB-pathway as a downstream therapeutic alternative in the treatment of Her2 overexpressing tumors and therapy-resistant disease in vitro and in vivo.
In vitro studies demonstrate that RB loss can modulate the response to a Her2/EGFR antagonist. Alternatively, results indicate that a novel therapeutic agent that specifically targets cyclin dependent kinase 4 and 6 (CDK4/6) activity dramatically and efficiently inhibits acini/cell growth. Furthermore, CDK4/6 inhibition prevents the formation of multiacinar structures characteristic of Her2 overexpression. Furthermore, a Her2 overexpressing mouse mammary tumor model was utilized to confirm our in vitro findings. These studies indicate that CDK4/6 inhibition was effective in suppressing tumor cell proliferation in vivo. Combined, these findings provide further insight into the crosstalk between Her2 signaling and cell cycle control in the context of therapeutic response, and introduce a novel mode of therapeutic intervention.
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 233. doi:10.1158/1538-7445.AM2011-233
Abstract 2344: Distinct combinations of signaling pathways promote migration of MDA-MB-231 breast carcinoma cells in response to different stimuli
Authors: Harrison Susan M. , Chen Min , Knifley Teresa , O'Connor Kathleen L. 
Published: June 2012

Abstract
Cancer cell invasion and metastasis are predicated on the activation of signaling pathways that control dynamic organization of cytoskeletal architecture. The coordinate reorganization of an actin network pushing at the leading edge and an actin-myosin mediated retraction at the rear of the cell facilitates cell polarity to allow directed movement. Motility of the highly invasive breast carcinoma cell line MDA-MB-231 is promoted by various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor (HGF) and epidermal growth factor (EGF). The goal of this project is to delineate the signaling pathways mediating motility in response to each of these stimuli. Identifying common and conditional pathways mediating cell motility has important implications for therapeutic intervention of cancer cell invasion and metastasis. We conducted migration, invasion, and morphology assays in the presence of inhibitors for pathways known to contribute to the cytoskeletal reorganization required for cell migration. LPA, HGF and EGF were evaluated for their capacity to signal through the Rho family small GTPases, Rho and Rac, the MAP kinase pathway via MEK1/2 and myosin light chain kinase (MLCK) to influence cell migration and invasion. LPA is a recognized component of breast cancer progression and potent stimulator of Rho activity, which has been extensively implicated in the migration of carcinoma cells in a variety of cancers including breast. Surprisingly, LPA-stimulated migration of MDA-MB-231 cells was not affected by Rho inhibitors but was instead sensitive to Rac inhibition. In contrast, Rho was required for HGF and EGF-stimulated migration of MDA-MB-231 cells while Rac had no effect on these processes. Other common pathways mediating cell motility including MLCK are used by all three chemoattractants. MDA-MB-231 cells employed all of the pathways examined for invasion, potentially reflecting the complexity of navigating in a three dimensional environment. These observations suggest that while multiple signaling pathways contribute to the migratory potential of a cancer cell, not all pathways are operating under all conditions. Different context-specific pathways may supplement a core of common pathways to create a functional signal but the characteristics of the response will likely rely on the particular combination used by the cell.
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 2344. doi:10.1158/1538-7445.AM2011-2344
Abstract 2355: Full-length wild-type CD99 increases the migration and invasiveness of human malignant glioma cells
Authors: Seol Ho Jun , Nam Do-Hyun , Lee Yu Jin , Smith Christian A. , Rutka James T. 
Published: June 2012

Abstract
The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass is considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed CD99, which is a transmembrane glycoprotein, is more expressed in malignant glioma than in normal brain. It has been implicated in cell adhesion and migration in various cells, even if the function of this gene is not understood clearly. This gene has two isoforms of wild-type and splicing variant.
We revealed that only wild-type CD99 is expressed in human glioma cells and tissues. Through MTS, colony-forming, and anoikis assays, we found that wild-type CD99 in glioma cells has enough resistance for anoikis and ability to survive and grow in anchorage independence, as is opposed to previous reports in other tumors. Using tissue microarray, we validated that CD99 demonstrates higher expression in gliomas compared to non-neoplastic brain. We inhibited CD99 expression by siRNA and demonstrated decreased glioma cell migration and invasion. In contrast, when CD99 was over-expressed in glioma cells, we observed enhancement of cell migration and invasiveness. Orthotopic brain tumor model with nude mice harboring CD99 overexpressing glioma cells results in significant decreased survival rate, compared to control mice. Moreover, higher invasiveness is observed in overexpressing mice by pathological review.
Taken together, our findings suggest that CD99 play an important role in the migration and invasion of human gliomas. CD99 could be a target to inhibit migration and invasion especially in CD99-expressing gliomas.
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 2355. doi:10.1158/1538-7445.AM2011-2355
Abstract 2362: Antimetastatic potential of the antiprogestin mifepristone in cancer cells
Authors: Brandhagen BreeAnn N. , Tieszen Chelsea R. , Telleria Carlos M. , Goyeneche Alicia A. 
Published: June 2012

Abstract
For most cancers, it is metastasis and burden of the secondary tumors that account for nearly 90% of cancer-related mortality. The process of metastatic dissemination of tumor cells is extremely complex. Among the critical parameters involved in metastatic spread are cellular detachment from the initial tumor, migration, invasion and adhesion to secondary sites, all processes associated with changes in cell morphology caused by cytoskeletal rearrangements. Our laboratory previously demonstrated that the synthetic antiprogestin mifepristone (MF) inhibits the growth of cancer cells of reproductive and non-reproductive origin. We also observed that in response to MF, the cells displayed drastic changes in morphology. Due the impact of cell structure on the metastatic process, this study questioned whether MF has anti-metastatic potential deregulating key processes required for metastatic dissemination. Cancer cell lines of the ovary (SK-OV-3), breast (MDA-MB-231), prostate (LNCaP), and brain (U87MG) were chosen from a panel of cell lines in which we previously observed cytostatic activity of MF associated with changes in cellular morphology. Cell cultures were exposed to vehicle or MF for 72 h at which point we examined the morphology of the cells, the distribution of cytoskeletal proteins actin and tubulin, the adhesion capacity to components of the extracellular matrix, and the cell migratory and invasive properties. MF induced distinct morphology changes after 48 h exposure, independent of the density of the cell culture population. Interestingly, MF induced similar morphology changes in all cell lines, which included shrinkage of the cell body, long, thin cellular extensions, and a loss of cell-to-cell connections. Morphology changes were associated with rearrangement of actin and tubulin filaments. Upon removal of MF, cell morphology and proliferation returned to that of untreated cultures in all cell lines expect for LNCaP. For all cell lines, MF caused accelerated trypsin-induced detachment and decrease in cell adhesion to various extracellular matrix substrates suggesting that MF may impair re-adhesion of cells en route to colonize a secondary location. Moreover, MF significantly inhibited the ability of cells to migrate in wound healing and Boyden chamber assays, as well as their capacity to invade through extracellular matrix-coated polycarbonate membranes. Overall this study suggests that antiprogestin MF could be of potential therapeutic use, not only as a cytostatic agent impairing tumor growth, but also to halt metastatic spread of tumor cells. (Supported by NCI grants K22CA121991 and K22CA121991S1).
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 2362. doi:10.1158/1538-7445.AM2011-2362
Abstract 2377: Variation in the BRCT1 domain of the DNA repair gene XRCC1 delays invasive breast cancer in mice
Authors: Pettan-Brewer Christina , Morton John , Coil Rebecca , Goh Jorming , Ladiges Warren C. 
Published: June 2012

Abstract
The breast cancer susceptibility protein BRCA1 C-terminal (BRCT) domain coordinates protein interactions in DNA repair and cell cycle control, and comprises over 100 member proteins. One of these, XRCC1, is involved in base excision repair and single strand break repair. In order to investigate the role of the XRCC1-BRCT1 domain in breast cancer, we generated a mouse line with a variation of leucine (L) from arginine (R) at position 360, and crossed it with PyMT transgenic mice with a highly penetrant metastatic breast cancer phenotype. PyMT mice with advanced tumors expressing the L360R variant (N=20) had an average tumor volume of 360±57 mm3 compared to an average tumor volume of 730±69 mm3 for PyMT/wild type littermates (N=20), significant at p less than 0.01. In addition, the L360R variant was associated with a significant decrease in metastatic foci in the lungs of PyMT mice, an increase in tumor cell apoptosis as measured by caspase 3 immunohistochemistry, a decrease in tumor cell proliferation as measured by ki-67 immunohistochemistry, and a decrease in PARP binding as determined by NADH depletion. These preliminary observations suggest that the XRCC1/BRCT1 domain is involved in invasive breast cancer, and that genetic variation of this domain can suppress the invasive phenotype by decreasing tumor cell proliferation and increasing apoptosis of tumor cells possibly in association with altered PARP binding and activity. The XRCC1 L360R mouse is a promising animal model to further investigate the potential of targeting the XRCC1/BRCT1 domain for adjunctive treatment of invasive breast 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 2377. doi:10.1158/1538-7445.AM2011-2377
Abstract 2396: Function of HLTF in the development of colon cancer and in the maintenance of genomic stability
Authors: Sandhu Sumit , Wu Xiaoli , Mai Sabine , Ding Hao 
Published: June 2012

Abstract
HLTF (Helicase like Transcription Factor) is a DNA helicase protein which is homologous to SNF/SWI family. It has also been shown to be a functional homolog of yeast rad5, required for the maintenance of genomic stability through the ubiquitination of proliferating cell nuclear antigen (PCNA). Although the physiologic role of HLTF is largely unknown, inactivation of HLTF by promoter methylation has been demonstrated in more than 40% human colon cancers. In this study, we have applied mouse transgenic approaches to determine whether loss of HLTF function could be important for colorectal carcinogenesis.
HLTF knockout mice were created by the deletion of first 5 exons of HLTF genome. The complete loss of HLTF expression in these mice was confirmed by Northern blot and RT-PCR assays. HLTF knockout mice did not show any developmental defects within a 2-year observation, indicating that HLTF is dispensable for normal development, and loss of HLTF function alone is not sufficient to drive colon carcinogenesis. To determine whether loss of HLTF function could cooperate with other tumor suppressors in the formation of colon cancers, we have bred HLTF knockout mice with the mutant mice for p53 and Apc (adenomtous polyposis coli). In HLTF−/−/Apc+/− mice, the significantly increased formation of intestinal adenocarcinoma and colon cancers were observed. Although very few HLTF−/−/p53−/− mice developed colon cancers, these mice had increased incidence of lymphoma formation. This finding suggests that loss of HLTF function could not only promote colon cancer formation, but also for other types of tumor. Cytogenetic analysis of colon cancer cells derived from HLTF−/−Apc+/− mice demonstrated a high incidence of gross chromosomal instabilities, including Robertsonian fusions, fragments and aneuploidy. All these genetic alterations were not observed in the intestinal tumor cells from Apc+/−, implicating that loss of HLTF function could induce genomic instability which contributes to colorectal carcinogenesis. To further establish the role of HLTF in the maintenance of genomic stability, we have also derived HLTF deficient mouse embryonic stem (ES) cells, and demonstrated that HLTF−/− ES cells exhibited similar, but a milder genetic alterations as observed in HLTF deficient colon cancer cells. Taken together, our work provides direct genetic evidence that loss of HLTF function as observed in a majority of human colon cancers is able to promote colorectal carcinogenesis. This function could be mediated by the induced genomic instability.
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 2396. doi:10.1158/1538-7445.AM2011-2396
Abstract 2401: Loss of Nkx3.1 cooperates with Myc overexpression to promote prostate tumorigenesis
Authors: McKissic Sydika , Roh Meejeon , Abdulkadir Sarki 
Published: June 2012

Abstract
Nkx3.1 is a homeodomain-containing transcription factor essential for prostate development and differentiation while loss mediates prostate tumor initiation. In mice, conditional loss of Nkx3.1 results in prostatic epithelial hyperplasia and prostatic intraepithelial neoplasia (PIN) formation. This increases the susceptibility of mice with compound mutations to the development of invasive adenocarcinoma. Human clinical data suggests that loss of Nkx3.1 and Myc overexpression are strongly correlated with increased tumor stage. Furthermore, Myc overexpressing transgenic mice lose Nkx3.1 in the PIN to carcinoma transition suggesting that Nkx3.1 loss is distinct and may provide a selective growth advantage. To further evaluate the cooperation between Nkx3.1 and Myc, we generated transgenic mice with prostate specific loss of Nkx3.1 and Myc overexpression. These mice contain a latent, Cre-activatable Myc allele and Nkx3.1 floxed alleles. Prostate specific Cre results in concurrent deletion of Nkx3.1 and activation of Myc. We have found that the young trigenic mice show advanced lesions compared to controls. High grade prostate intraepithelial neoplasia (HGPIN) was evident as early as 15 weeks of age. By 35 weeks of age, these mice show multi-focal HGPIN lesions with micro-invasive cancer. An increase in proliferation and a modest increase in apoptosis are also seen. Complementary prostate regeneration studies further support this progressive phenotype. We hypothesize that Nkx3.1 and Myc are cooperating to promote prostate tumorigenesis by regulating important cancer genes. Future studies are being conducted to identify the mechanism of cooperation between Nkx3.1 and Myc.
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 2401. doi:10.1158/1538-7445.AM2011-2401