bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A60: Role of telomere dysfunction in the premature cellular senescence of Hutchinson-Gilford progeria syndrome
Authors: Benson Erica K. , Aaronson Stuart A. 
Published: May 2012

Abstract
Introduction: Telomere dysfunction promotes genomic instability and is often associated with loss of tumor suppressor gene function and tumorigenesis. Conversely, in aging, telomere dysfunction is hypothesized to mediate cellular senescence by activating intact tumor suppressor pathways. Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging syndrome caused by a dominant mutation in the nuclear lamina intermediate filament protein lamin A that leads to a truncated and permanently farnesylated protein termed progerin. Progerin expression is associated with early cellular senescence involving shortened telomeres and increased DNA damage. Herein, we investigated whether telomere dysfunction contributes to the DNA damage accumulation and premature cellular senescence phenotypes observed with cells from HGPS patients.
Methods: Using HGPS cell lines from patients or normal fibroblasts ectopically expressing progerin, we investigated the effects of telomerase on cell growth, senescence, p53 and Rb tumor suppressor pathway activation, and DNA damage. We also determined whether progerin-induced DNA damage localized to telomeres.
Results: We demonstrate that addition of telomerase, which has been reported to immortalize HGPS fibroblasts, abrogated premature senescence, reduced p53 and Rb tumor suppressor pathway activation, and decreased the DNA damage phenotype. These effects of telomerase required both its catalytic and DNA binding activities. Furthermore, progerin-DNA damage signaling localized to telomeres indicating that progerin causes damage at telomeres.
Conclusions: These results establish that progerin causes a defect in telomere maintenance linked to a chronic DNA damage response that activates tumor suppressor genes and induces the HGPS premature senescence phenotype.
Citation Information: Cancer Res 2009;69(23 Suppl):A60.
Abstract A63: Inhibition of ROCK signaling prevents breast cancer metastasis to human bone
Authors: Liu Sijin , Goldstein Robert H. , Scepansky Ellen M. , Rosenblatt Michael 
Published: May 2012

Abstract
ROCK signaling plays a fundamental role in regulating cell morphology, adhesion and motility. Aberrant expression of ROCK is related to tumor metastases and correlates with poor clinical outcome. However, the molecular mechanisms responsible for ROCK-mediated effects and the potential utility of ROCK inhibition as a therapeutic target have not been fully investigated. Here, we show that ROCK expression is increased in metastatic human breast cancer (BrCa) cell lines and clinical mammary tumors compared to non-metastatic cell lines and tumors. Inhibition of ROCK activity, either by a specific ROCK inhibitor (Y27632) or ROCK-targeted siRNAs, reduces BrCa cell migration and proliferation in vitro. We evaluated the effect of ROCK inhibition on metastasis to bone in vivo using a novel “human BrCa metastasis to human bone” mouse model. Metastases to human bone cores (hBCs) were inhibited in Y27632-treated mice (5 out of 14, 36%) compared to control mice (8 out of 12, 67%), based on luminescent imaging. The overall frequency of metastasis to mouse skeleton in Y27632-treated mice was reduced by 36% compared to controls. Moreover, the mass of metastatic tumors in the mouse skeleton was diminished by 77% (P&lt;0.05) in Y27632-treated mice. ROCK1 siRNAs also decrease the frequency of BrCa metastasis to hBCs and mouse skeleton, but to a lesser extent than Y27632. We demonstrate that ROCK's effects on tumor cell invasion/motility and growth may derive from regulating the actin-myosin cytoskeleton, modulating the c-Myc pathway by increasing the stabilization of c-Myc protein via phosphorylation, and targeting c-miRNAs. Coupled to increased c-Myc, expression of the c-Myc-regulated miR-17-92 cluster is shown here to be elevated in metastatic BrCa cells compared to non-metastatic cells, and diminished upon Y27632 treatment. Furthermore, blockade of miR-17 is shown to decrease BrCa cell invasion/migration in vitro and metastasis in vivo. Collectively, these findings suggest that augmented ROCK signaling contributes to BrCa metastasis in at least 3 ways, by 1) regulating the actin cytoskeleton and actin-myosin-dependent contractility; 2) targeting mRNAs controlled by the transcription factor c-Myc to potentiate cell growth and viability; and 3) modulating the expression of certain miRNAs, such as the c-Myc-regulated oncogenic miR-17-92 cluster. Inhibition of ROCK-mediated signaling appears to be a promising and potentially specific approach to suppress the occurrence of bone metastases in BrCa.
Citation Information: Cancer Res 2009;69(23 Suppl):A63.
Abstract A64: Calprotectin suppresses PIWIL1 and tumor growth in oral squamous cell carcinoma
Authors: Khammanivong Ali , Sorenson Brent , Guenther Brian , Ross Karen F. , Herzberg Mark C. 
Published: May 2012

Abstract
Calprotectin (a heterodimer of S100A8 and S100A9), normally expressed in oral epithelial cells, is down-regulated in oral squamous cell carcinoma (OSCC). Carcinoma cells over-expressing calprotectin show reduced tumor growth in vivo and in vitro and are morphologically more differentiated than carcinoma cells negative for calprotectin expression. Phosphorylation of histone H3 at serine 10 (Ser10) is a marker for increased cell division, CD24 is expressed on differentiated cells and PIWIL1 plays a role in cellular self-renewal.
Objective: To determine the molecular pathways involved in calprotectin-associated suppression of tumor growth and self-renewal.
Methods: To study the regulatory function of calprotectin in tumor growth, a non-calprotectin expressing human epithelial carcinoma cell line (KB) was transfected with either an empty vector (KB-EGFP) or vector containing S100A8 and S100A9 genes (KB-S100A8/A9). To study the loss of function, S100A8 and S100A9 expression was silenced in calprotectin-positive OSCC cell line (TR146) by small interfering RNA. Genome wide analysis of gene regulation was compared between calprotectin-negative and calprotectin-positive KB cells using Affymetrix HG-U133A microarrays and validated by quantitative real-time RT-PCR. Changes in protein expression were examined by immunofluorescence flow cytometry.
Results: Calprotectin expression in carcinoma cells increases phosphosphorylation of histone H3 (Ser10) correlating with a larger population at the cell cycle checkpoint G2/M and significant reduction in growths in vitro (KB-S100A8/A9 and TR146) and in vivo (KB-S100A8/A9). Among the cellular differentiation-associated molecules, expression of CD24 is significantly up-regulated, whereas, the expression of self-renewal factor PIWIL1 is reduced at both mRNA and protein levels when calprotectin is over-expressed.
Conclusion: Calprotectin may play essential roles in suppressing tumor growth by decreasing self-renewal capability and maintaining cellular differentiation. Loss of calprotectin expression in OSCC may lead to unregulated growth and de-differentiation. This study was supported by the NIH/NIDCR grant R01DE11831.
Citation Information: Cancer Res 2009;69(23 Suppl):A64.
Abstract A66: K12/SECTM1 promotes melanoma tumor progression via upregulation of integrin β3 expression
Authors: Wang Tao , Lopez-Coral Alfonso , Roesch Alexander , Huang Catherine , Cha In-Chul , Hwang Wei-Ting , Meyer Stefanie , Vogt Thomas , Herlyn Meenhard , Kaufman Russel E. 
Published: May 2012

Abstract
Metastatic melanoma is a leading cause of mortality in skin cancers with few therapeutic options. However, molecular mechanisms underlying melanoma tumorigenesis and metastasis remain poorly understood. Here, for the first time, we have determined a specific role of K12/SECTM1(SECTM1) in melanoma pathogenesis. Microarray analysis of melanoma revealed that SECTM1 is higher expressed in melanoma cell lines compared to melanocytes. We confirmed that SECTM1 was upregulated in most melanoma cell lines both at the transcriptional and post-transcriptional level. In addition, SECTM1 is highly expressed in patient melanoma lesions both in primary and metastasis samples. Furthermore, overexpression of SECTM1 in melanoma cell line WM3899 dramatically increased cell invasion in vitro, and promoted tumor growth and metastasis in vivo. Consistently, reduction of SECTM1 expression in melanoma cell line WM9 inhibited tumor growth and metastasis in vivo. Mechanistically, SECTM1 upregulated expression of integrin β3 (ITGβ3), thus contributing to the progressive phenotype of SECTM1 in melanoma. Hence, this study identified SECTM1 as a novel melanoma metastasis gene. We anticipate that our findings will provide new avenues in the pathogenesis of melanoma metastasis and that targeting of SECTM1 could be a novel approach to inhibit melanoma progression.
Citation Information: Cancer Res 2009;69(23 Suppl):A66.
Abstract A73: Understanding specificity in Notch receptor signaling
Authors: Bell Alisa , Okamura Heidi , Keane David , Perino Samantha , Lorusso Jeanine , Gyuris Jeno , O'Hagan Ronan 
Published: May 2012

Abstract
Notch signaling plays an integral role in cell growth and differentiation. Alterations in Notch signaling caused by mutations in receptors, amplification of pathway components, and increased expression of receptors and ligands have been shown to be important in tumor growth and maintenance. There are multiple Notch receptors and multiple ligands that can potentially interact to elicit a signal. Furthermore, many tumor cells express more than one Notch receptor. The complexity of these interactions and the potential specificity of resultant signals necessitate further understanding of the context of signaling to better determine how to treat Notch driven tumors. To this end, we have developed cell based reporter assays to investigate total Notch signal from cells stimulated by cell surface ligands in a co-culture system or by plate-bound ligands. In addition, we have developed assays to determine signal from individual Notch receptors. Human cancer cell lines that express multiple Notch receptors were engineered to express a Notch-dependent luciferase reporter. These cells were stimulated with plate-bound or cell surface ligands and assayed for activation of the Notch receptors. Subsequently, specific blocking of individual Notch receptors with antibodies was used to determine which specific receptors acted as effectors of Notch signal. Understanding both the array of Notch receptors on a particular cell type and more specifically the ability of each receptor to produce active signal will be important in determining how to effectively treat Notch driven tumors.
Citation Information: Cancer Res 2009;69(23 Suppl):A73.
Abstract A76: A novel in vivo model for pancreatic restructuring and suppression of transformation
Authors: DiRenzo Daniel , Shi Guanglu , Konieczny Stephen F. 
Published: May 2012

Abstract
Our studies are focused on the identification and prevention of the initial transformation events associated with pancreatic ductal adenocarcinoma (PDA) development, an extremely lethal malignancy with poor prognosis and ineffective treatments. PDA initiates through activating mutations in the KRAS proto-oncogene (KrasG12D) and recent studies from our laboratory have determined that targeted expression of an endogenous KrasG12D allele in pancreatic acinar cells is sufficient to produce PDA precursor lesions (PanINs). These results suggest that PDA arises via acinar cells undergoing a process of acinar-to-ductal metaplasia (ADM) which is characterized by a loss of acinar cell properties with the acquisition of duct-like characteristics. Several studies indicate that the process of ADM requires inactivation of the acinar-specific transcription factor Mist1, since Mist1 null (Mist1KO) mice display accelerated ADM and PanIN formation upon KrasG12D expression. Additionally, acinar cell polarity is disrupted in Mist1KO mice with diffuse zymogen granule organization and mis-localization of nuclei. These results suggest that Mist1 has a key role in suppressing PDA formation by maintaining the acinar cell differentiation program. To identify the downstream genes affected by the absence of Mist1, we have generated an inducible Mist1 transgenic mouse line (LSL-Mist1myc) in which constitutive Mist1 expression is activated through Cre-mediated recombination. When LSL-Mist1myc mice are crossed to Mist1Cre-ER mice, Mist1myc expression can be induced in acinar cells upon Tamoxifen (TM) addition. Analysis of Mist1Cre-ER/Cre-ER; LSL-Mist1myc mice confirmed that exogenous Mist1myc expression is detected as early as 6 hours post-TM. Time course studies in a Mist1KO background revealed that nuclear and zymogen granule organization can be restored within 24 hours of Cre activation. We conclude that Mist1 actively controls pancreatic acinar cell organization and that induction of Mist1 in Mist1KO mice leads to complete reorganization of pancreatic tissues. Our current efforts are focused on establishing how Mist1 negatively regulates ADM and PanIN formation and to identify Mist1 targets that negatively regulate Kras-induced pancreas metaplasia and transformation.
Citation Information: Cancer Res 2009;69(23 Suppl):A76.
Abstract A78: Sgt1 heterozygous mutation suppresses phenotypes of p53-null mice
Authors: Sakuraba Yoshiyuki , Ohta Satoshi , Kitagawa Katsumi 
Published: May 2012

Abstract
Sgt1 is an Hsp90 co-chaperone that is highly conserved among species, from yeast to humans. In vitro studies using siRNA and small-molecule inhibitors have indicated that Sgt1 is required for kinetochore assembly, proper localization of the spindle checkpoint proteins during mitosis, and genomic stability in humans. In vivo studies using knockout (KO) mice have revealed that kinetochore and spindle checkpoint genes are related to tumorigenesis. To examine the in vivo functions of Sgt1 gene in mammals, especially in tumorigenesis, we generated and analyzed Sgt1 KO mice by using a gene-trap line.
No Sgt1 homozygous KO mice were obtained from heterozygous intercrosses, even in E8.5 embryos, suggesting that Sgt1 homozygous mice are early embryonic lethal. In contrast, Sgt1 heterozygous mutants grew normally and did not exhibit any obvious phenotypes. We are now monitoring carcinogen-induced and spontaneous tumorigenesis in Sgt1 heterozygous mutants. We generated Sgt1 p53 double mutants in order to enhance the phenotypes associated with tumorigenesis. p53 is a major tumor suppressor gene, and p53 −/− KO mice usually die when they are approximately 20 weeks old, mainly because of lymphoma. Interestingly, Sgt1+/− p53−/− double mutants, especially females, survive significantly longer than p53−/− single mutants, suggesting that the Sgt1 heterozygous mutation suppresses p53−/− -induced tumorigenesis. In addition to the survival phenotype, the unequal gender ratio (more males than females) in p53−/− mutants was also overcome by the Sgt1 heterozygous mutation.
These results suggest that the Sgt1 heterozygous mutation suppresses the p53 KO phenotypes not only in tumorigenesis but also in embryonic development defects of females. We are currently examining whether the female infertility in p53−/− is also suppressed by the Sgt1 mutation. We will discuss how Sgt1 suppresses the p53 phenotypes at the meeting.
Citation Information: Cancer Res 2009;69(23 Suppl):A78.
Abstract B10: A novel mechanism of prostate cancer metastasis through the PDGF D/β-PDGFR axis
Authors: Najy Abdo J. , Saliganan Allen , Bonfil Daniel , Kim Hyeong-Reh C. 
Published: May 2012

Abstract
Cancer metastasis is a multi-step process permitting malignant cells to invade into a secondary niche. Prostate cancer has a high prevalence of bone metastasis where 90% of diagnosed cases exhibit metastatic bone lesions. Analysis of these metastatic tissues revealed that PDGFRβ (platelet-growth factor receptor β) is upregulated and activated in 80% of the cases. This receptor was thought to be stimulated by its classical ligand PDGF B. However, within bone metastatic prostate cancer, PDGF B is not detected, suggesting another ligand may exist for PDGFR β. Recently, a new PDGF family member, PDGF D, was identified and shown to bind to and activate PDGFR β. Using Oncomine data analysis and immunohistochemical analysis, we demonstrated upregulation of PDGF D in metastatic prostate cancer. To investigate the role of PDGF D in bone metastasis, we established several prostate cancer cell lines engineered to overexpress PDGF D. We observed an increase in prostate carcinoma cell migration as well as adhesion on osteoblast deposited matrix in response to PDGF D upregulation. Cell surface integrins are known to play a crucial role in cell migration and adhesion. Our studies revealed that PDGF D overexpression modulated α1 and α3 expression to mediate the cancer cell malignant phenotype. In the intratibial metastatic mouse model, PDGF D enhanced prostate cancer tumorigenesis and resulted in osteoblastic lesions. Consistent with our in vivo findings, we found that PDGF D supports osteoblast proliferation and differentiation in vitro. Taken together, we propose that PDGF D contributes to prostate cancer bone metastasis through tumor cell surface integrin modulation and stimulation of stromal components within the bone microenvironment.
Citation Information: Cancer Res 2009;69(23 Suppl):B10.
Abstract B11: Cyclin D1 overexpression antagonizes Notch inhibition in the esophageal squamous epithelium
Authors: Nakagawa Momo , Wong Gabrielle , Ohashi Shinya , Natsuizaka Mitsuteru , Vega Maria E. , Stairs Doug B. , Rustgi Anil K. 
Published: May 2012

Abstract
Cyclin D1 overexpression is common in esophageal squamous cell carcinoma (ESCC) and other squamous cell cancers. Notch signaling is implicated in cell proliferation and differentiation, and may act as a tumor suppressor. While squamous differentiation is maintained in ESCC and its precursor lesions, the role of Notch in esophageal carcinogenesis remains elusive. The role of genetic interactions between cyclin D1 and the Notch signaling were explored in this study. Immortalized human esophageal cells EPC2-hTERT (keratinocytes) were retrovirally transduced with tetracycline-regulatable (tet-cyclin D1. Notch was activated by the Notch1 intracellular domain and inhibited by dominant negative mastermind-like1 (DN-MAML1), a genetic pan-Notch inhibitor. Notch activity was assessed by a 8xCSL-luciferase reporter assay. Quantitative RT-PCR, Western blotting and immunohistochemistry were performed. The squamous epithelium was reconstituted in organotypic (3-D) culture, a form of tissue engineering. Notch activation led to inhibition of cell proliferation and terminal differentiation in EPC2-hTERT with a robust induction of involucrin (an early differentiation marker). By contrast, DN-MAML1 inhibited the ICN-induced CSL-dependent transcriptional activity and Notch target genes, including Hey1, Hes5 as well as involucrin. In organotypic culture, the parental EPC2-hTERT cells formed a well-organized stratified squamous epithelium. In organotypic culture, DN-MAML did not affect basal cell proliferation, but severely impaired squamous maturation and terminal differentiation with loss of filaggrin expression (a late differentiation marker) in the suprabasal layer. In 3-D culture, Cyclin D1 overexpression resulted in basal cell hyperplasia and antagonized the DN-MAML1 effect. Thus, cyclin D1 appears to stimulate cell proliferation while restraining the Notch-mediated squamous differentiation.
Citation Information: Cancer Res 2009;69(23 Suppl):B11.
Abstract B14: The novel function and trafficking mechanism of nuclear ErbB-2
Authors: Li Long-Yuan , Chen Hsiuyi , Hsieh Yi-Hsien , Wang Ying-Nai , Chu Hsiao-Ju , Hung Mien-Chie 
Published: May 2012

Abstract
We have demonstrated that ErbB-2 translocates into the nucleus through importin β1—mediated nuclear import by endosomal sorting, and transactivates transcription of cyclooxygenase-2 which has been known to be involved in tumor progression and metastasis, suggesting nuclear ErbB-2 may also contribute to the tumor malignancy. However, how the membranebound ErbB-2 can be released from the lipid bilayer and translocates into the nucleus; and the biological functions of the nuclear ErbB-2 are not yet completely understood. Here, we have identified novel ErbB-2-interacting nuclear proteins. The interplay between nuclear ErbB-2 and interacting protein was investigated, which may elucidate a novel function of nuclear ErbB-2 in contributing to tumorigenesis. In addition, ErbB-2 interacts with endoplasmic reticulum (ER) proteins, Sec61α, a subunit of Sec61 channel, and EDEM. Sec61α and EDEM are known to mediate retrotranslocation of misfolded proteins in the ER to the cytosol (called ER-associated degradation pathway). We have demonstrated that Sec61α and EDEM also play important roles in retrotranslocation of ErbB-2 to the cytosol and to the nucleus, suggesting part of ER retrotranslocation pathway is likely involved in nuclear trafficking of ErbB-2. [This work was supported by National Health Research Institutes NHRI-EX98-9603BC, National Science Council NSC952311-B-039-002 and NSC 97-3111-B-039-004 and Department of Health DOH97-TD-I-111-TM003 and DOH98-TD-I-111-TM002 (to LYL)].
Citation Information: Cancer Res 2009;69(23 Suppl):B14.
Abstract B28: Trisomy suppress tumorgenesis in the NP-cis tumor model
Authors: Yang Annan , Reeves Roger 
Published: May 2012

Abstract
Down syndrome results from trisomy for human chromosome 21 (chr21). People with DS have an increased risk of getting leukemia, but the likelihood of solid tumors might be reduced by contribution of several genes. We showed that trisomy in Ts65Dn “Down syndrome” mice reduces tumor number in the ApcMin model of intestinal cancer and that tumor number is inversely proportional to copy number of the Ets2 gene [Sussan TE, Nature 451, 73–75]. The current study provides evidence for additional dosage sensitive tumor repressor gene(s) in the cancer model, NP-cis. These mice carry a single copy of both the tightly linked Nf1 and p53 genes in cis. Tumors form by LOH. When NP-cis mice were crossed with Ts65Dn, trisomic offspring survived significantly longer than euploid. In contrast to the intestinal adenoma finding, introduction of a null allele of Ets2 in either trisomic or euploid mice (resulting in 2 or one copies of Ets2, respectively) had no effect on survival. This result demonstrates further dosage effects of genes trisomic in these mice and in Down syndrome. The lack of Ets2 effect in the NP-cis model is consistent with a protective mechanism that involves up-regulation of p53 by Ets2, thereby sensitizing trisomic cells to p53-mediated apoptosis. This mechanism would not work in NP-cis since tumors form due to loss of p53. In this regard, in vitro analysis of fibroblast cell lines from several genotypes showed that trisomic cells expressing more Ets2 than euploid were more sensitive to induction of apoptosis by camptothecin and showed a higher frequency of senescence. Other genes, like Endostatin, a cleavage product of Col18a1, and Rcan1 have been shown to inhibit angiogenesis in adosage dependent manner in xenograft models of tumor growth [Zorick TS, EJHG 9, 811-4, Baek KH, Nature 459, 1126-30]. In contrast to results from xenografted tumors, endogenous tumors formed in trisomic, NP-cis mice showed no reduction in angiogenesis. Our findings indicate that multiple mechanisms involving other genes trisomic in Ts65Dn mice likely contribute to reduced tumor incidence in Down syndrome.
Citation Information: Cancer Res 2009;69(23 Suppl):B28.