bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-289: A novel role for the p19ARF tumor suppressor in chromosome segregation
Authors: Britigan Eric MC , Weaver Beth A. 
Published: August 2012

Abstract
The p19ARF tumor suppressor (p14ARF in humans) is part of the ink4a locus and has been implicated in a variety of cancers. The traditional role for p19ARF has been in the stabilization of p53, a protein which is inactivated or mutated in 50% of tumors. However, it has been suggested that p19ARF has roles outside of this pathway. Evidence for this comes from mouse model studies that found mice lacking p19ARF and p53 develop a wider tumor spectrum and are more likely to have multiple tumors than mice lacking p53 alone. We have found that loss of p19ARF in mouse embryonic fibroblasts (MEFs) leads to a weakened mitotic checkpoint and aneuploidy. The mitotic checkpoint is the major cell cycle checkpoint regulating chromosome segregation and progression through mitosis. Defects in chromosome segregation produce progeny that are aneuploid, meaning they contain an abnormal chromosome number that deviates from a multiple of the haploid. The majority of cancers are aneuploid, which suggests that a dysfunctional mitotic checkpoint could play a role in tumorigenesis or cancer progression. In addition to a weakened mitotic checkpoint, loss of p19ARF leads to other mitotic defects including multipolar spindles, supernumerary centrosomes, and lagging chromosomes in anaphase. Future work will define the mechanism by which p19ARF functions in mitosis and establish an additional role in which p19ARF acts as a tumor suppressor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-289. doi:1538-7445.AM2012-LB-289
Abstract LB-29: LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap
Authors: Nguyen Hoa B. , Babcock Justin T. , Wells Clark D. , Quilliam Lawrence A. 
Published: August 2012

Abstract
The liver kinase B1 (LKB1) tumor suppressor inhibits cell growth through its regulation of cellular metabolism and apical-basal polarity. The best understood mechanism whereby LKB1 limits cell growth is through activation of the AMP-activated-protein-kinase/mammalian-target-of-rapamycin (AMPK/mTOR) pathway to control metabolism. Since LKB1 is also required for polarized epithelial cells to resist hyperplasia it is anticipated to function through additional mechanisms. Recently, Yes-associated protein (Yap) has emerged as a transcriptional co-activator that modulates tissue homeostasis in response to cell-cell contact. Thus this study examines a possible connection between Yap and LKB1. Restoration of LKB1 expression in HeLa cells, which lack this tumor suppressor, or shRNA knockdown of LKB1 in 293T cells, demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion, and proteasomal degradation. The ability of phosphorylation-defective Yap mutants to rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest that Yap inhibition contributes to LKB1 tumor suppressor function(s). Interestingly, LKB1 inhibited Yap independently of either AMPK or mTOR activation. These findings reveal a novel mechanism whereby LKB1 may restrict cancer cell growth via the inhibition of Yap.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-29. doi:1538-7445.AM2012-LB-29
Abstract LB-293: High-throughput proteomic analysis identifies protein s as a modulator of high grade and castrate-resistant prostate cancer
Authors: Saraon Punit , Jarvi Keith , Diamandis Eleftherios P. 
Published: August 2012

Abstract
High-Throughput Proteomic Analysis Identifies Protein S as a Potential Modulator of Castrate-Resistant Prostate Cancer Punit Saraon, Daniela Cretu, Colm Morrissey, Keith Jarvi, Eleftherios P. Diamandis Androgen-deprivation remains the principal therapy for advanced and metastatic prostate cancers. However, some cancer cells can survive this treatment and transform themselves to a more aggressive androgen-independent prostate cancer (AIPC). An understanding of the molecular alterations that occur during the progression to androgen-independence is an integral step to generate effective targeted therapies. Using Mass Spectrometry, we compared the proteomes of androgen independent cell lines (PC3, DU145, PPC1, LNCaP-SF, 22Rv1) to androgen-dependent (LNCaP, VCaP) and normal prostate epithelial (RWPE) cell lines. We identified more than 100 proteins that were differentially secreted in the androgen independent cell lines, based on spectral counts. Of these, Protein S (PROS1) was elevated in the secretomes of all of the AIPC cell lines, with no detectable secretions in normal and androgen dependent cell lines. Using qPCR, we observed significantly higher tissue expression levels of PROS1 in prostate cancer samples (p&lt;0.05), further indicating its importance in prostate cancer progression. Similarly, immunohistochemistry analysis revealed elevation of PROS1 during high grade prostate cancer (Gleason ≥ 8), and further elevation in castrate-resistant metastatic prostate cancer lesions. We also observed its elevation in high grade prostate cancer seminal plasma samples (P&lt;0.05). To understand the functional role of PROS1 with respect to prostate cancer progression, we generated stable PROS1 knock-downs in DU145 cells, and performed cell migration and viability assays. In-vitro scratch assays measuring cell migration and proliferation revealed that PROS1 enhanced growth of prostate cancer cells, as there was significantly reduced wound closure in shPROS1 DU145 cells compared to scrambled control cells (p&lt;0.05). In addition, cell viability assays showed that shPROS1 cells had reduced survival rates compared to scrambled cells when treated with the chemotherapeutic agents, docetaxel and paclitaxel, indicating its role as a potential anti-apoptotic factor. Taken together, our preliminary results show that PROS1 is elevated during high grade and castrate-resistant prostate cancer, and promotes prostate cancer migration and cell survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-293. doi:1538-7445.AM2012-LB-293
Abstract LB-299: Prognostic impact of EMT (epithelial-mesenchymal-transition) related protein expression in endometrial cancer
Authors: Tanaka Yoshimichi 
Published: August 2012

Abstract
Objectives: Epithelial-mesenchymal-transition (EMT) is recently identified as a important step in the invasion and metastasis of cancer. In this process, a critical molecular feature is the down regulation of E-cadherin and which is controled mainly by the Snail-related zinc-finger transcription factors (Snail and Slug). The aim of this study is to evaluate the prognostic impact of EMT related protein (E-cadherin, Snail and Slug) expression in endometrial cancer. Methods: We perfomed immunohistochemical annalysis using tissue microarray samples of 354 primary tumors and 30 metastases of endometrial carcinomas, and investigated the relationship between protein expression, clinicopathologic features and outcomes. Results: Reduced E-cadherin was seen in 39.8% in primary tumors. In endometrioid adenocarcinoma, reduced E-cadherin was seen in 19.5%, 40.8% and 72.7% in G1, G2 and G3 tumors, respectively. Nuclere expression of Snail was positive in 16.9% in primary tumors. Both redeced E-cadherin and nuclear expression of Snail were significantly associated with histological type, FIGO stage, myometrial invasion, ascites positive, lymph node metastasis and patient survival (P&lt;0.01). Nuclear expression of Slug was seen in only 3.7% in primary tumors. Allmost all cases of Slug positive were carcinosarcomas, therefore, it was also associated with patient survival (P&lt;0.01). We couldn't find any differencies in the rates of reduced E-cadherin and nuclear expression of Snail/Slug between in the primary tumors and metastases. In multivariate analysis, nuclear expression of Snail or Slug was found to be a significant predictor for both the progression free survival and overall survival (P&lt;0.01). Conclusions: These data indicate that reduced E-cadherin and nuclear expression of Snail and Slug have a prognositic impact in endometrial cancer. Therefor, to clarify and control of EMT signaling is a promising molecular targeting therapy in endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-299. doi:1538-7445.AM2012-LB-299
Abstract LB-300: The role of WNT7B in prostate cancer bone metastasis
Authors: Zheng Dali , Zhou Tianhua , Decker Keith F. , Wang Kaidi , Jia Li 
Published: August 2012

Abstract
Prostate cancer is the most common cancer for men in the US. It is well known that the androgen receptor (AR), a master transcription factor in prostate, plays a critical role in all stages of prostate cancer. There has been a dedicated interest in identification of downstream AR target genes responsible for prostate cancer growth and progression. Using chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq), we identified WNT7B as a direct AR target gene in both androgen-dependent LNCaP and androgen-independent C4-2B cells. Knockdown of WNT7B by RNA interference inhibits the growth of LNCaP and C42B cells, accompanied by a corresponding increase in apoptosis as determined by Caspase-3 and -7 activities. Overexpression of WNT7B promotes the growth of C4-2B cells in the absence of androgen. One of the major challenges in prostate cancer research is the propensity for bone metastasis, which displays characteristic osteoblastic lesions. Since WNT7B plays an important role in bone formation, we asked whether prostate cancer-produced WNT7B induces osteoblast differentiation using an in vitro model of the murine osteoblast precursor ST2 cell line. We found that in a co-culture system, overexpression of WNT7B in LNCaP and C42B cells induces osteoblastic differentiation of ST2 cells, as indicated by increased alkaline phosphatase production, bone sialoprotein (an early marker for osteoblast differentiation) expression, and mineralization. On the other hand, knockdown of WNT7B in prostate cancer cells inhibits the differentiation of ST2 cells. These results indicate that WNT7B can stimulate the growth of prostate cancer cells as an autocrine agent and induce osteoblastic differentiation in bone metastases as a paracrine agent. WNT7B may be a potential therapeutic target for prostate cancer bone metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-300. doi:1538-7445.AM2012-LB-300
Abstract LB-301: Galectin-3 contributes to melanoma metastasis by regulating Autotaxin through NFAT1
Authors: Braeuer Russell R. , Zigler Maya , Kamiya Takafumi , Dobroff Andrey S. , Huang Li , Bar-Eli Menashe 
Published: August 2012

Abstract
Melanoma is the deadliest form of skin cancer in which patients with metastatic disease have a five year survival-rate of less than 10%. Recently the over expression of a beta galactoside binding protein, Galectin-3, has been correlated with metastatic melanoma. Yet its role in melanoma progression is not completely understood. We have previously demonstrated that silencing Galectin-3 in melanoma cell lines leads to decreased melanoma cell invasion and migration in vitro and inhibits tumor growth and metastasis in vivo via the regulation of VE-cadherin and IL-8. To determine whether Galectin-3 can enhance the expression of other genes involved in the metastatic phenotype, a cDNA microarray analysis was performed after silencing Galectin-3 in melanoma cell lines. One of the many genes down regulated after silencing Galectin-3 is the lysophospholipase D enzyme Autotaxin. Autotaxin expression enhances melanoma migration and invasion by converting Lysophosphatidylcholine (LPC) to Lysophosphatidic acid (LPA) within the tumor microenvironment. LPA binds to EDG family G-protein coupled receptors to initiate downstream signaling which drives invasion and metastasis. Here we show that Galectin-3 regulates Autotaxin expression at the transcriptional level. Moreover, silencing Galectin-3 decreases total protein expression of the transcription factor NFAT1 which reduces its binding to the Autotaxin promoter. This in turn decreases Autotaxin promoter activity and protein expression. Therefore, Galectin-3 is required to maintain NFAT1 protein expression which enhances Autotaxin transcription and induces angiogenesis, tumor growth, and metastasis of melanoma cells. This is the first report to connect Galectin-3 with Autotaxin and LPA synthesis along with assigning an important role for NFAT1 in melanoma metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-301. doi:1538-7445.AM2012-LB-301
Abstract LB-302: Coordinate upregulation of pluripotency factors in a hybrid epithelial/mesenchymal state in anoikis resistant suspended breast epithelial cells
Authors: Grosse-Wilde Anne , Ozinsky Adrian 
Published: August 2012

Abstract
Epithelial cells have an absolute requirement for surface adhesion for survival, and loss of adhesion activates apoptosis, a process named anoikis. During metastasis, cancerous epithelial cells are able to survive anoikis after they have spread from the primary site of the tumor. The mechanisms underlying anoikis survival are not well understood, but include cell lineage switching from epithelial to mesenchymal behavior, implying a role for stem cells. Several studies have shown that the mesenchymal population of tumorigenic breast cells contains stem cells, yet it appears that only a small yet unknown subpopulation of the mesenchymal cells is able to survive the strong selection pressure to survive anoikis in suspension and proliferate to form mammospheres. These studies have been complicated by the fact that heterogeneous cell lines consisting of epithelial and mesenchymal cells were analyzed, obscuring the role of small but possibly relevant subpopulations. Here, we were employing both single cell-derived homogeneous mesenchymal cell clones as well as novel microfluidics-based high throughput qRT-PCR analysis to unravel gene expression in epithelial and/or mesenchymal breast cancer cells during survival of anoikis. We show evidence that during culture of transformed mammary epithelial cells (HMLER) in suspension certain subpopulations disappear and then get repopulated by the surviving, proliferating and differentiating subpopulation in suspension. During this period in suspension critical for repopulation we find coordinate expression of both epithelial and mesenchymal markers, rapid upregulation of pluripotency factors (such as OCT4 and Nanog), as well as of several other genes that have previously been described to indicate poor prognosis for breast cancer survival. Those poor prognosis markers we also found elevated in replated and passaged anoikis-resistant HMLER cells as well as in HMLER-derived mesenchymal clones. By contrast expression of pluripotency factors was only restricted to the suspended state. In conclusion, here we show that in suspended breast epithelial cells there exists an epithelial/mesenchymal hybrid state likely to give rise to differentiated progenies, being able to adapt to the diverse challenging environments such as at secondary metastatic sites in cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-302. doi:1538-7445.AM2012-LB-302
Abstract LB-303: Metastasis suppression by MDM2 binding protein through inhibition of ACTN4 function
Authors: Iwakuma Tomoo 
Published: August 2012

Abstract
MDM2 Binding Protein (MTBP) has been implicated in cancer progression. Our previous results demonstrate that MTBP haploinsufficiency in mice enhances cancer metastasis. Recently, loss of MTBP expression is shown to be associated with reduced survival of patients with head and neck carcinoma, and serves as an independent prognostic factor when p53 is mutated in tumors. Here we demonstrate one mechanism by which MTBP inhibits cancer metastasis. Overexpression of MTBP in human osteosarcoma cell lines lacking wild-type p53 did not alter primary tumor growth in mice but significantly inhibited metastases. MTBP downregulation increased the migratory potential of Mdm2-/-p53-/- mouse embryonic fibroblasts, suggesting that MTBP inhibited cell migration independently of the MDM2-p53 pathway. Co-immunoprecipitation and mass spectrometric analysis identified alpha-actinin-4 (ACTN4) as a MTBP-interacting protein. Endogenous MTBP interacted with and partially colocalized with ACTN4. MTBP overexpression inhibited cell migration and filopodia formation mediated by ACTN4. Increased cell migration by MTBP downregulation was inhibited by concomitant downregulation of ACTN4. MTBP also inhibited ACTN4-mediated F-actin bundling. We furthermore demonstrated that nuclear localization of MTBP was dispensable for inhibiting ACTN4-mediated cell migration and filopodia formation. Thus, MTBP suppresses cell migration, at least partially, by inhibiting ACTN4 function. Our study not only provides a mechanism of metastasis suppression by MTBP, but also suggests MTBP as a potential biomarker for cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-303. doi:1538-7445.AM2012-LB-303
Abstract LB-304: Sp1 expression regulates lung tumor progression
Authors: Hsu Tsung-I , Hung Jan-Jong 
Published: August 2012

Abstract
The role of Sp1 in controlling gene expression in lung tumor development and metastasis is not well understood. In this study, we showed that the Sp1 level was highly increased and required for lung tumor growth in transgenic mice bearing Kras-induced lung tumors under the control of doxycycline. Furthermore, the Sp1 level was highly upregulated in lung adenocarcinoma cells with low invasiveness and in patients with stage I lung cancer. We also demonstrated that Sp1 was downregulated in lung adenocarcinoma cells with high invasiveness and in patients with stage IV lung adenocarcinoma. Moreover, Sp1 inversely regulated migration, invasion and metastasis of lung adenocarcinoma cells in vivo. In addition, a decrease in the Sp1 level in highly invasive lung adenocarcinoma cells resulted from instability of the Sp1 protein. Furthermore, overexpression of Sp1 in highly invasive lung adenocarcinoma cells increased expression of E-cadherin, a suppressor of metastasis, and attenuated the translocation of β-catenin into the cellular nucleus which leads to tumor malignancy. Taken together, Sp1 level accumulated strongly in early stage and then declined in late stage, which is important for lung cancer cell proliferation and metastasis during tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-304. doi:1538-7445.AM2012-LB-304
Abstract LB-429: Dormant cancer cells contribute to residual disease in a mouse model for reversible pancreatic cancer
Authors: Lin Wan-Chi , Rajbhandari Nirakar , Liu Chengbao , Sakamoto Kazuhito , Batra Surinder , Opavsky Rene , Felsher Dean , Hollingsworth Michael , Hebrok Matthias , Rui Hallgeir , Wagner Kay-Uwe 
Published: August 2012

Abstract
The initiation and progression of premalignant lesions into pancreatic ductal adenocarcinomas (PDACs) is governed by a series of genetic changes, but it is still unknown whether these alterations are still required for the maintenance of primary and metastatic PDAC. Here we show that the c-Myc oncogene is upregulated throughout the entire process of neoplastic progression in human PDAC. To address whether this oncogene is essential for the growth and survival of cancer cells, we developed a novel mouse model that allows a temporally and spatially controlled expression of c-Myc in pancreatic progenitors and derived lineages of the exocrine pancreas. Upregulation of c-Myc is sufficient to cause adenocarcinomas after a short latency, and haploinsufficiency in Cdkn2a dramatically increases the rate of metastasis. Despite a macroscopically complete regression of primary, metastatic, and transplantable tumors following the downregulation of c-Myc, some cancer cells remain dormant. A significant number of these residual neoplastic cells express cancer stem cell markers, and re-expression of exogenous c-Myc leads to rapid cancer recurrence. Collectively, the results of this study suggest that c-Myc plays a significant role in the progression and maintenance of PDAC, but additional therapeutic strategies are necessary to eradicate residual cancer cells to prevent cancer relapse.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-429. doi:1538-7445.AM2012-LB-429