bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 314: Characterization of the Y83C Gab1 mutation in breast cancer
Authors: Holgado-Madruga Marina , Badal Shawn , Wong Albert J. 
Published: February 2011

Abstract
Following addition of various growth factors and cytokines, the Gab1 docking protein is tyrosine phosphorylated, which then activates different signaling pathways. A screening of human breast cancers revealed a mutation in the Pleckstrin homology domain of Gab1, at the 83rd amino acid changing the tyrosine to a cysteine. To explore the impact of this mutation in human breast cancer, the mutation was overexpressed in the MDA-MB 468 cell line. Upon addition of EGF there was a significant higher increase in tyrosine phosphorylation of the mutant versus the wild type that correlated with an increased association with Shc, Shp2, Grb2 and p85. Pull down experiments with the GST/RBD (Ras binding domain of Raf) fusion protein detected higher activity levels of Ras in the mutant form in comparison with the wild type. Soft agar colony formation assays indicated a 2-3 fold increase in the number of colonies in the Y83C mutation with respect to the wt Gab1. The information understood from this study can help to characterize a mutant of Gab1 and this plays an important role in the context of personalized medicine by elucidating a specific target against tumors which express the mutation.
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 314.
Abstract 3168: Knock down of m-calpain in a mouse breast carcinoma cell line reduced tumor growth in mouse engraftment studies and compromises the Akt pathway and in vitro cell migration
Authors: Ho Wai-chi , Greer Peter A. 
Published: February 2011

Abstract
Calpains are a family of calcium-dependent intracellular cysteine proteases consisting of fourteen members, with µ- and m-calpains (calpain 1 and 2) being ubiquitously expressed. Calpains play crucial roles in a various cellular functions including cell survival, movement and calcium homeostasis. Abnormal expression or activation of calpain is linked to pathological conditions such as neurodegenerative diseases, tumor growth and metastasis, platelet malfunction and muscular dysfunction. Studies have showed that calpain is involved in retraction of focal adhesions at the rear of migrating cells, indicating a major role of calpain in cell movement and cytoskeletal organization. In addition, calpain may be a key component in regulating cell survival and gene expression.
We have examined the role of m-calpain in tumor growth. Mouse mammary carcinoma cells AC2M2 were transduced with a lentiviral vector expressing shRNA directed against m-calpain or a control shRNA. A mouse xenograft experiment was then carried out by injecting control cells or m-calpain knockdown cells into the mammary fat pads of nude mice. Preliminary results showed that mice injected with m-calpain knockdown cells grow smaller tumors. In vitro transwell migration assay showed that the m-calpain knockdown cells migrated slower than the control cells. Furthermore, biochemical studies demonstrated that these AC2M2 m-calpain knockdown cells have reduced activation of key the survival mediator Akt, although there was no significant difference in the growth rate between the knockdown and the control cells. Other biochemical studies implicate the transcription factor Foxo, a downstream target of Akt, in mediating the m-calpain-regulated tumor progression through activation of transcription of genes that are important in cell survival such as p27 Kip1 and Bim. In summary, our current data suggests that m-calpain mediates tumor growth through regulation of Akt signaling. This in turn regulates Foxo in the activation of gene transcription during cell survival signaling.
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 3168.
Abstract 3182: Decreased expression of PTEN enhances CXCR4-mediated proliferation and tumorigenesis in prostate cancer cells
Authors: Chetram Mahandranauth A. , Hinton Cimona V. 
Published: February 2011

Abstract
The progression of human prostate cancer is a result of metastasis from the primary tumor to vital organs. Metastasis is a complex process that involves invasion, intravasation, extravasation, and metastatic colonization. To date, the biology underlying the various mechanisms of metastasis has not been fully elucidated. Chemokines are pro-inflammatory molecules that bind to chemokine receptors, which are members of the G-protein coupled receptor (GPCR) family. The interaction between chemokines and their receptors results in a diverse array of biological and biochemical functions, such as chemotaxis, hematopoiesis and angiogenesis. Likewise, neoplastic cells employ chemokines and their receptors to promote metastasis, and encourage cell survival. It has been observed that the CXCR4 chemokine receptor is overexpressed on the cell surface of prostate cancer cells, which directed metastatic cells to tissues where its CXCL12 ligand is overexpressed, such as the bones and lungs. The Phosphate and Tensin homolog deleted on chromosome 10 (PTEN) is the second most mutated tumor suppressor in human cancer, and has been shown to be mutated in metastatic prostate cancer cells. Gao et al demonstrated that reconstituted PTEN in lymphocytes down-regulated CXCR4-mediated chemotaxis towards its ligand, CXCL12. Additionally, progenitor PTEN-deficient smooth muscle cells (SMC) increased migration towards CXCL12-producing SMC, suggesting that an alteration in PTEN expression negatively regulated CXCR4-mediated events. We analyzed prostate cancer cells for the expression of CXCR4 by flow cytometry, and observed that CXCR4 was expressed in human metastatic prostate cancer cell lines, PC3 and LnCaP. We analyzed for the expression of PTEN, and observed no expression of PTEN in PC3 and LnCaP cells at the protein level by western blot, nor at the mRNA level in PC3 cells by PCR. Furthermore, when reconstituted with PTEN, PC3 cells demonstrated a mesenchymal to epithelial-like phenotypic change in morphology. Additionally, we observed that reconstituted PTEN inhibited CXCR4-meditated proliferation via an MTT assay. Therefore, we hypothesize that the absence of PTEN expression correlates with an up-regulation of CXCR4-mediated proliferation and tumorigenesis in prostate cancer cells. In summary, our results showed that PTEN induced an epithelial-like morphological change, and inhibited CXCR4-mediated proliferation in metastatic prostate cancer cell lines. In future studies, we will investigate if the reconstituted expression of functional PTEN regulates CXCR4-mediated metastatic events in prostate cancer cells.
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 3182.
Abstract 3201: Identification of the type 2 cystatins (SA/SN) as a novel biomarkers for stress-induced senescence in human non-small cell lung cancer lines
Authors: Cheng Guanjun , Wang Liang-Chuan S. , Crisanti Cecilia , Sun Jing , Kapoor Veena , Albelda Steven M. 
Published: February 2011

Abstract
Purpose: Stress-induced cellular senescence (SIS) is becoming increasingly well recognized as an important process in premalignant neoplastic lesions and the response to chemotherapeutic drugs and radiation. In addition, senescent cells may release growth factors, cytokines, proteases, and other factors that affect the tumor microenvironment. The standard maker of SIS (staining for β-galactoside [β-gal] at pH 6) cannot be used in fixed tissues. New and more consistent biomarkers of SIS that could be used in tissue sections are thus needed to improve early detection of premalignant lesison, to design and monitor cancer therapeutic approaches, and to gain additional mechanistic understanding.
Experimental Procedures: Doxorubicin (Dox) was employed to induce senescence in A549 and L55 human non-small cell lung cancer lines. Gene expression profiles were compared in control vs Dox-treated A549 cells. Validation was carried out by real time quantitative PCR (qPCR). Type 2 Cystatin (SA/SN) protein expression levels were evaluated by immunoblotting and immunohistochemistry (IHC) using an antibody (Santa Cruz) that recognized both proteins.
Results: Dox induced senescence of A549 and L55 cells as evidenced by cellular enlargement, cessation of proliferation, and positive staining for ß-gal at pH 6.0. Microarray screening revealed marked upregulation of the genes for Cystatin SA and SN, that was confirmed by qRT-PCR. High protein expression levels of type 2 cystatin (SA/SN) was demonstrated in Dox-treated cells by immunoblotting and IHC. IHC was successful in ethanol-fixed and formalin-fixed paraffin embedded slides.
Conclusions: The cystatin superfamily is a well-established family of cysteine protease inhibitors that have been suggested to affect cell differentiation, growth, and migration through protease inhibition and by direct receptor mediated effects. The role of cystatin SA/SN in SIS is under study. However, our results identify two Type 2 Cystatins (SA/SN) that appear to be promising biomarkers for SIS in human non-small cell lung cancer. Cystatin staining could be utilized in fixed tissue sections to screen for oncogene-induced premalignant lesions and for studying the effects of chemotherapeutic drugs and radiation in lung cancer or bronchial biopsy samples.
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 3201.
Abstract 3214: C-strand fill-in at human telomeres requires lagging strand synthesis machinery and is essential for maintaining functional telomeres
Authors: Chai Weihang , Huang Chenhui 
Published: February 2011

Abstract
Telomeric single-stranded G-overhangs are required for protecting chromosome ends and for telomerase elongation of telomeres. However, the molecular mechanism for G-overhang generation at human telomeres is unclear. We report here that G-overhangs undergo cell cycle-regulated dynamic changes independent of telomerase activity. G-overhangs are lengthened during S phase due to extensive C-strand resection, and shortened at G2 phase as a result of C-strand fill-in. This delayed C-strand fill-in is mediated by lagging-strand polymerases and regulated by cyclin-dependent kinase 1. Inhibiting C-strand fill-in induces telomere DNA damage response and a G2 arrest, suggesting a critical role of proper G-overhang generation in maintaining genome stability. In addition, the last nucleotide at C-strand remains precisely defined throughout the cell cycle. Our results indicate that both C-strand resection and fill-in are strictly regulated during the cell cycle to ensure proper G-overhang generation, and unveil an essential role of C-stand fill-in in maintaining functional telomeres.
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 3214.
Abstract 3227: Lung-targeted expression of B-RAF V600E in alveolar type II cells causes emphysema and delayed adenoma in mice
Authors: Zanucco Emanuele , Potapenko Tamara , Götz Rudolf , Carraretto Irene , Ceteci Fatih , Rapp Ulf R. 
Published: February 2011

Abstract
Classically oncogenes are found associated with neoplastic diseases. More recently a connection with developmental syndromes has been reported. Here we describe a link between the most prevalent mutant form of B-RAF oncogene (B-RAF V600E) with Chronic Obstructive Pulmonary Disease (COPD) that often precede lung cancer in men. By use of targeted expression of this mutant B-RAF in type II pneumocytes of mice we have developed an animal model for these devastating diseases that are epidemic worldwide. Constitutive expression of B-RAF V600E led to emphysema as early as late embryonic development that is persistent throughout adult life when it is often accompanied by chronic inflammation. Infiltrating immune cells include localized macrophages, mast cells, and leukocytes as in the case of human COPD. Inflammatory cell infiltration does not precede emphysema formation but is a prelude to tumor development. Consistently, ablation of RAG1 alleles did not eliminate emphysema or late tumor development. The oncogene involved in tumor formation is also B-RAF V600E because the most frequent mutations of spontaneous lung adenomas in mice were absent. These data support a model where the regenerative process triggered by continuous emphysema formation is the driving force that converts B-RAF V600E from a latent to an active oncogene in this target cell type. Our data suggest that B-RAF V600E is not a complete oncogene in type II cells and requires promoting conditions that can be provided by emphysema.
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 3227.
Abstract 3233: Inhibition of aldose reductase prevents lung cancer cell growth in vitro and in vivo
Authors: Ramana Kota V. , Tammali Ravinder , Singhal Sharad S. , Awasthi Sanjay , Srivastava Satish K. 
Published: February 2011

Abstract
Lung cancer is the second most common cancer and the leading cause of cancer death among both men and women. Although, tobacco smoking is the dominant etiologic factor responsible for the vast majority of lung cancers, other factors such as asbestos, pollutants, polycyclic aromatic hydrocarbons, nutritional and dietary factors which can cause pulmonary inflammation can also drive carcinogenesis by altering cellular and molecular targets and pathways that are crucial to normal tissue homeostasis. However, the molecular signaling events specific to the pulmonary inflammation and their effects on pulmonary cells leading to carcinogenesis are poorly understood. Hence, we investigated the role of polyol pathway enzyme aldose reductase (AR), an oxidative stress response protein that catalyzes the reduction of lipid peroxidation -derived lipid aldehydes and their glutathione conjugates, in the mediation of carcinogenic signals leading to lung cancer. We examined the effect of pharmacological and siRNA -mediated inhibition of AR on in vitro human lung carcinoma cell line A549 growth as well as tumor growth in nude mice xenografts. We have also examined the molecular mechanisms by which AR inhibition prevents carcinogenic signaling events that cause lung cancer cell growth. Treatment of A549 cells with AR inhibitors prevented the activation of NF-kB and expression of NF-kB- dependent inflammatory markers such as iNOS and Cox-2. AR inhibition also prevented the proliferation of cultured human lung cancer cells. Further, AR inhibition significantly arrested the tumor growth in nude mice bearing lung adenocarcinoma xenografts. Similar results were observed in AR-siRNA treated nude mice xenografts. Immunohistochemical analysis of nude mice tumor cross sections indicated that AR inhibition prevents activation of iNOS, Cox-2, AR and NF-kB. Our studies thus strongly suggest that AR may be a critical regulator of signaling pathway(s) that cause lung cancer. Hence, disrupting these signals by AR inhibition could be a novel preventive approach in lung 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 3233.
Abstract 3239: Synergy of PIM1 kinase with c-MYC in prostate cancer
Authors: Wang Jie , Kim Jongchan , Roh Meejeon , Franco Omar E. , Martinez Erin , Hayward Simon W. , Wills Marcia L. , Abdulkadir Sarki A. 
Published: February 2011

Abstract
The oncogenes PIM1 and c-MYC are frequently up-regulated in human prostate tumors. We found that PIM1 and c-MYC were co-expressed in human prostate cancer and were associated with higher Gleason scores. We next used a model of prostate regeneration coupled with lentiviral-mediated gene transfer to directly show that Pim1 dramatically enhanced c-MYC tumorigenicity in naïve adult mouse prostatic epithelium in a kinase-dependent manner. Microarray analysis revealed that many signaling pathways including MAPK, focal adhesion calcium signaling pathway were activated in MYC/Pim1 tumor. Knockdown of Pim1 in MYC/Pim1 tumor derived cell line reduced ERK and Akt phosphorylation. We further showed that targeting Pim1 by shRNA inhibited tumorigenicity in vitro and in vivo. Pim1 kinase inhibitor quercetagetin also inhibited cell growth in vitro. These results directly demonstrate that MYC and PIM1 cooperate in promoting tumor development. PIM1 can be considered as a drug target for human prostate cancer treatment.
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 3239.
Abstract 3243: Differential effects of caloric and carbohydrate restriction upon prostate cancer tumor growth in a mouse model
Authors: Thomas Jean A. , Masko Elizabeth M. , Antonelli Jodi A. , Pooulton Susan H. , Phillips Tameika E. , Coburn Tonisha , Freedland Steve J. 
Published: February 2011

Abstract
Background: Caloric restriction (CR) has been shown to be anti_cancer. However, whether these effects are the result of generalized reduction in overall caloric intake or reduced intake of macronutrients (i.e. carbohydrates) are unknown. We sought to investigate the differential effects of caloric and carbohydrate restriction upon prostate cancer tumor growth in a xenograft model.
Materials and Methods: A total of 100 male SCID mice were injected subcutaneously with the LAPC-4 cell line. Mice were randomized to 1 of 4 diets: ad libitum Western diet (WD, 49% carbohydrates, 35% fat, and 16% protein), pair-fed No Carbohydrate Ketogenic Diet (NCKD; 1% carbohydrates, 83% fat, 16% protein), Western diet calorically restricted (WD-CR), and NCKD calorically restricted (NCKD-CR). Calorically restricted arms were fed 75% of the calories of their reference diet group. Tumor volumes and body weights were measured twice weekly. Mice were sacrificed when tumor volumes reached 1,000 mm3.
Results: Relative to WD, there was a suggestion of smaller body weights in both NCKD-CR and WD-CR arms (rank-sum, p≤0.06). There was trend for heavier mice in the NCKD group (rank-sum, p=0.09). By day 50, median tumor volumes for NCKD, WD-CR, and NCKD-CR were 45, 51, and 62% smaller than WD (rank-sum, all p≤0.001). At any time point, there were no significant differences in tumor volume among the NCKD, NCKD-CR, and WD-CR arms. However, there was a suggestion of smaller tumors in the NCKD-CR arm by day 42 relative to NCKD and WD-CR (p&lt;0.11). Diet was significantly associated with mouse survival (log_rank, p=0.004). In 2_way comparisons, NCKD, NCKD-CR, and WD-CR had significantly prolonged survival relative to WD (log_rank, all p≤0.02). However, no difference in survival was seen among any caloric or carbohydrate restricted arms (log rank, p≤0.16). A total of 34 mice died due to infection prior to their tumors reaching 1,000mm3 and therefore were not included in the survival analyse (WD-CR, n=14; NCKD, n=5; NCKD-CR, n =15).
Conclusions: Both CR and carbohydrate restriction without weight loss are effective in delaying tumor growth and improving mouse survival. We found no differences between caloric and carbohydrate restricted arms, though this may relate to loss of study power due to mouse infections. CR may further weaken the immune system of immunocompromised mice subjecting them to increased risk of infections. A confirmatory study is underway in a high-level barrier facility.
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 3243.
Abstract 3247: Establishment of a castration-resistant prostate cancer model, JDCaP-hr: Implications for prostate cancer recurrence
Authors: Nakata Daisuke , Masaki Tsuneo , Tanaka Akira , Kakoi Yuichi , Nakayama Yusuke , Kusaka Masami , Watanabe Tatsuya 
Published: February 2011

Abstract
There are few in vivo models of androgen-dependent prostate cancer (ADPC), and limited availability of the models makes it difficult to evaluate anticancer agents for early stage prostate cancer and to investigate the recurrence of ADPC. We previously reported JDCaP xenograft model, an ADPC model with wild type androgen receptor (AR) and TMPRSS2-ERG gene fusion, derived from skin metastatic lesions of a prostate cancer patient. JDCaP xenografts completely regressed after surgical or medical castration; however, some of them relapsed several months after castration. The relapsed JDCaP subline, designated JDCaP-hr (hormone refractory), was established by serial passage in castrated nude mice. The AR antagonist bicalutamide did not show any effect on tumor growth of JDCaP-hr, while testosterone treatment induced tumor regression of JDCaP-hr, indicating that ligand binding to AR is not necessary, rather cytotoxic, for the growth of JDCaP-hr. Direct sequencing analysis of full length AR revealed that JDCaP-hr retained wild type AR. AR mRNA expression in JDCaP-hr was approximately 7-fold higher than in JDCaP, and interestingly, truncated AR protein with molecular weight of approximately 75 kDa in addition to full length AR (110 kDa) was expressed in JDCaP-hr. Microarray analysis revealed that ubiquitin-dependent protein catabolism pathway was markedly upregulated in JDCaP-hr compared with JDCaP. JDCaP-hr cells proliferated in vitro in steroid-free medium under co-culture condition with mouse stromal cells, and secreted prostate-specific antigen into the conditioned medium. Taken together, JDCaP/JDCaP-hr is a valuable model which simulates the recurrence of ADPC to castration-resistant prostate cancer (CRPC) with common clinical features such as AR overexpression. This model provides not only useful in vivo and in vitro systems to evaluate anticancer agents for ADPC and CRPC but also intriguing implications for the recurrence of ADPC.
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 3247.