bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1107: Mutant p53 increases epithelial mesenchymal transition, estrogen receptor alpha and erbB2/Her2/neu
Authors: Strasberg- Rieber Mary , Rieber Manuel 
Published: February 2011

Abstract
OBJECTIVES.- Progression of carcinomas involves transition from an epithelial cobblestone-like cytoarchitecture to an elongated, mesenchymal phenotype., leading to an epithelial to mesenchymal transdifferentiation (EMT) (1). Since the p53 tumor suppressor pathway is inactivated in most human cancers due to gene mutations or dysfunction, we now investigated in human wt p53 breast carcinoma cells, whether EMT and cell proliferation are influenced by introducing a dominant-negative (DN) R175H mutant p53 (2). This mutation occurring in the p53 zinc-binding domain, is common to breast cancer patients poorly responsive to therapy (2) METHODS.- .- Fluorescence microscopy was used to determine EMT-linked decreases in E-cadherin and cytokeratin 18. These changes and others associated with EMT, were verified by immune blotting. Laser scanning cytometry was used to measure expression of ErbB2 and estrogen receptor alpha, cell cycle profile and proliferation (2). RESULTS.- Cells transduced with the DN-R175H mutant p53, increased expression of the mesenchymal marker vimentin and proliferation-associated cyclin A, also showing a greater G2 population which correlated with increased c-neu/Her2/ErbB2. Joint cytometric analysis of the Ki67proliferation marker and estrogen receptor alpha revealed a greater number of estrogen receptor-positive proliferating cells (3) among the mesenchymal population harbouring the DN-R175H mutant p53 .CONCLUSIONS.- These results suggest that EMT induced by the DN-R175H mutant p53 promotes a gain of pro-oncogenic function by increasing the % of proliferating cells expressing estrogen receptor alpha (3) and the expression of erbB2 (4)
REFERENCES
1.-Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009 119: 1420-8.
2.- Rieber M, Strasberg Rieber M. DN-R175H p53 mutation is more effective than p53 interference in inducing epithelial disorganization and activation of proliferation signals in human carcinoma cells : role of E-cadherin. Int J Cancer. 2009; 125:1604-12.
3.- Shoker BS, Jarvis C, Clarke RB, Anderson E, Hewlett J, Davies MP, Sibson DR, Sloane JP. Estrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol 1999, 155:1811-1815.
4.- Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B, Brisken C, Minucci S, Di Fiore PP, Pelicci PG. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009; 138:1083-95.
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 1107.
Abstract 1130: ING4 tumor suppressor binds to a transcription co-activator, CCAR1, and modulates estrogen-dependent cell growth and gene expression
Authors: Dempsey Katherine , Whitsett Timothy G. , Kim Suwon 
Published: February 2011

Abstract
The tumor suppressor ING4 (Inhibitor of Growth family member 4) has been shown to play a role in diverse cancer-related cellular processes including gene regulation, apoptosis, cell migration, contact inhibition, and angiogenesis. Deletion or reduced expression of ING4 has been shown in various human malignancies including breast cancer, suggesting the tumor suppressive role of ING4. ING4 has been shown to interact with a number of proteins in different cell types, that include p53, NFkB, p300, HBO1-HAT complex, and HPH1. However, the binding partner(s) relevant to the ING4 tumor suppressor function in breast cancer have not been identified. We employed a bacterial two-hybrid screening system using the N-terminal half of the ING4 protein as bait and identified a number of candidate ING4 binding proteins (IBPs). One of the candidate IBPs was CCAR1 (Cell-Cycle and Apoptosis Regulator Protein 1). CCAR1 has recently been characterized as a transcriptional coactivator that is required for estrogen-induced gene expression and cell growth in human breast cancer cells (Kim JH, Yang CK, Heo K, Roeder RG, An W, and Stallcup MR, Mol Cell, 2008). We show the full length ING4 co-immunoprecipitated with endogenous CCAR1 in MCF7 breast cancer cells. In addition, we show that overexpression of ING4 blocked estrogen-dependent cell proliferation of MCF7 cells. These results indicated that ING4 directly binds to CCAR1 and may antagonize the CCAR1 activity required for estrogen-dependent cell growth. We conclude that ING4 may function as a tumor suppressor in breast cancer by modulating estrogen/CCAR1-dependent cell proliferation and gene transcription.
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 1130.
Abstract 1131: ING4 attenuates breast cancer cell growth in Matrigel by altering Wnt/beta-catenin signaling pathway
Authors: Raymond-Whish Stefanie L. , Kim Suwon 
Published: February 2011

Abstract
ING4 is a member of the INhibitor of Growth (ING) tumor suppressor family, which plays a role in various cellular processes and suppresses hallmarks of cancer. ING4 contains a plant homeodomain (PHD) finger motif that has been implicated in transcriptional regulation via chromatin remodeling. However, the molecular mechanism(s) of ING4 tumor suppressor function is not known. In breast cancer, the ING4 locus is deleted in 10-20% of primary tumors, suggesting its role as a tumor suppressor. To better understand tumor suppressive function of ING4 in breast cancer, we tested whether ING4 can influence cell growth in three-dimensional culture environment using Matrigel. We found that ING4 retarded proliferation of T47D human breast cancer cells in Matrigel. In order to identify downstream target genes of ING4 that may be responsible for this activity, we employed gene expression profiling assays. The results showed that ING4 down-regulated several genes in the Wnt/β-catenin pathway, including Wnt4, Wnt6, dishevelled 1, dishevelled 3, and frizzled 4. Deregulation of the Wnt/β-catenin signaling pathway has been shown in human breast cancer as well as to induce mammary tumors in mice. We conclude that ING4 attenuates T47D cell growth in Matrigel by down-regulating the Wnt/β-catenin signaling pathway. Our data suggests that ING4 may function as a tumor suppressor in breast cancer by suppressing Wnt/β-catenin signals.
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 1131.
Abstract 1145: Analysis of circulating tumor cells from castrate resistant prostate cancer patients captured via a microfluidic device using the prostate specific membrane antigen antibody
Authors: Loftus Matthew , Gleghorn Jason , Pratt Erica , Bander Neil , Nanus David , Kirby Brian , Giannakakou Paraskevi 
Published: February 2011

Abstract
Prostate cancer (PC) is the most common type of cancer in males and the second leading cause of male cancer deaths in the United States. Circulating tumor cells (CTCs) are commonly found in the blood of patients suffering from mestatic disease and the capture of these cells is important in the study of disease progression. Existing devices use the EpCAM antibody which can capture circulating epithelial cancer cells, but also leads to a large number of leukocyte contamination. We have developed a microfluidic chip functionalized with an antibody to the prostate-specific membrane antigen (PSMA), which captures prostate CTCs with high purity and efficiency. This chip is designed with a staggered obstacle array that maximizes the CTC-wall interactions while minimizing the interactions with the other cells in the blood. PSMA-positive or -negative PC cells were spiked into blood from healthy donors, and we calculated capture rates to be ∼80%. Next, blood samples from patients (n = 20) with castrate resistant prostate cancer (CRPC) were run through the device and CTCs were captured and enumerated. CTCs were found in 90% of samples tested with the number captured averaging 27 ± 4 cells per mL of blood with a capture purity of 62 ± 2%. We plan to use this device to elucidate the molecular basis of CRPC clinical response to taxane treatment, which is the only class of chemotherapy drugs shown to improve survival in this type of PC. Previous data from our laboratory has shown that taxane treatment of PC cells inhibits the ligand-induced androgen receptor (AR) nuclear accumulation and transcriptional activation of androgen response element (ARE) containing genes including the prostate-specific antigen (PSA). These results implicate microtubules (MTs) in AR trafficking and suggest that the clinical activity of taxanes in CRPC may be mediated in part by the drugs’ ability to stabilize MTs and inhibit AR transcriptional activity. We plan to capture CTCs using the PSMA-specific microfluidic device from CRPC patients receiving taxane treatment and analyze them for AR subcellular distribution and correlate clinical response to taxane treatment. Our microfluidic device is a novel, specific, and improved technology to capture prostate CTCs that will allow us to better define the molecular basis of taxane treatment in CRPC patients.
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 1145.
Abstract 1159: Single molecule sequencing to detect and characterize somatic mutations in cancer genomes
Authors: Mardis Elaine , Maupin Rachel , Travers Kevin , Chin Chen-Shan , Eid John , Chau Benson , Londry Jason , Baybayan Primo , Magrini Vince , McLellan Mike , Wylie Todd 
Published: February 2011

Abstract
One result of large-scale cancer genome characterization is the identification of sets of genes that are commonly mutated in specific tumor types or subtypes and have clinical relevance, e.g. are prognostic or diagnostic. In this paradigm, we have investigated the use of a novel, single molecular real time (SMRT) sequencing technology from Pacific Biosciences that enables targeted regions to be sequenced in real time as single molecules in a mixed population. Several experiments were performed to evaluate the performance of this technology in the context of testing for cancer-specific mutations in previously characterized samples. In the first experiment we assessed whether SMRT sequencing could detect the known mutations of PCR products derived from genomic DNA of tumor cells compared to normal cells. In the second experiment we investigated the impact of different neoplastic cellularity percentages on the ability to detect known mutations. The final experiment involved producing deep read count SMRT sequencing data from PCR products containing known variants to ascertain their different levels of prevalence in a discrete tumor cell population, and then comparing these results to deep read counts for the same variants obtained with the Illumina instrument. Our results indicate that the Pacific Biosciences instrument offers exquisite sensitivity and speed in detecting somatic single base mutations in tumor-derived genomic DNAs.
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 1159.
Abstract 1163: Sensitive and specific detection of clinically relevant proteins in human testicular germ cell tumors using proximity ligation and quantitative PCR
Authors: Looijenga Leendert H. , Gillis Ad J. , Stoop Hans , Bierman Katharina , Swartzman Elana , Ferlinz Astrid , Oosterhuis Wolter J. , Shannon Mark 
Published: February 2011

Abstract
Human testicular germ cell tumors (TGCTs) are the most frequent solid cancer in Caucasian males between the ages of 15 and 45 years. In spite of the high success rate of current treatment strategies (surgery, irradiation and chemotherapy), TGCTs are the second leading cause of death in this age group. The initiating event, leading to carcinoma in situ (CIS), occurs during embryonal development, offering a window of opportunity for early detection and intervention, thereby preventing the need for intensive (systemic) treatment. CIS is the malignant counterpart of a primordial germ cell, and can be effectively diagnosed using immunohistochemisty for OCT3/4, NANOG, c-KIT and its ligand (stem cell factor, SCF). In addition, SOX17 and SOX2 are informative for the diagnosis of the invasive components seminoma and embryonal carcinoma. Currently, in a clinical setting, these proteins are detected using predominantly immunohistochemistry, an approach that is labor-intensive and non-quantitative. Here we present data on the detection of these proteins using a novel qPCR-based method, Taqman Protein Expression Assay, which is based on the Proximity Ligation Assay (PLATM) technology. The method was first validated on negative controls and a series of TGCT-derived cell lines with efficient siRNA-induced down-regulation of the targets, an informative system for investigating stem cell regulatory circuits. Subsequently, the assay was further developed to enable analysis of both snap frozen and formalin-fixed paraffin-embedded (FFPE) tissues. The assays were found to be fast (results in less than 1 day), highly reproducible (SD less than 0.2 CTs), sensitive (able to detect target protein from as few as 10-100 cells, depending on the level of expression of the protein under investigation), and quantitative. Taqman Protein Expression Assays therefore allow the systematic analysis of multiple proteins within a single small sample in a high throughput set up, and offer unique opportunities for sensitive, specific and quantitative protein detection in both experimental and clinical studies.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 1163.
Abstract 1172: RARB is a biomarker of poor prognosis in prostate carcinomas
Authors: Alves Flavia C M C , Drigo Sandra A. , Rainho Cláudia A. , Camargo João L V , Fonseca Francisco P. , Soares Fernando A. , Trindade-Filho José C S , Domingues Maria A C , Rogatto Silvia R. 
Published: February 2011

Abstract
Purpose: Despite the advances in prostate carcinomas (PCa) management, about 30% of the patients who undergo radical prostatectomy presented biochemical recurrence (BCR). BCR is considered an unfavorable prognostic factor followed by clinical disease progression. The current prognostic markers in PCa are unable detect correctly who is at risk for BCR. Hypermethylation at RARB and RASSF1A genes have been associated with worse prognosis in PCa. The current study aimed to evaluate RARB, and RASSF1A hypermethylation frequencies in prostate carcinoma (PCa) and to correlate these alterations with down-regulation at transcriptional and protein levels and with clinical outcome.
Methods: Methylation patterns of RARB and RASSF1A were determined by methylation-specific PCR in 68 PCa samples and 27 non-neoplastic prostate tissues. Gene expression was evaluated by quantitative RT-PCR in 73 PCa, 15 adjacent non-neoplastic prostate tissues (AdjP) and two normal prostate (N). Protein expression was evaluated in an independent PCa cohort (n=141) with long-term follow-up period. The findings were associated with clinicopathological parameters and BCR-free survival (BRFS).
Results: RARB and RASSF1A genes were hypermethylated in PCa (P &lt;0.0001 and P = 0.0017, respectively). RASSF1A mRNA and protein levels were similar in PCa and AdjP samples. Down-expression of RARβ in transcript (P=0.001) and protein (P=0.0007) levels were detected in PCa. Lower mRNA levels were associated with RARB hypermethylation. Nuclear and cytoplasmic RARβ protein expression was detected in tumor tissues. Multivariate analysis demonstrated that cytoplasmic RARβ immunostaining was independently associated with decreased BRFS (P=0.005, HR=2.314).
Conclusions: RARB hypermethylation seems to be one of the mechanisms involved in RARβ down-expression in PCa. Cytoplasmic RARβ protein is an independent predictor of poor prognosis that may be considered a new biomarker in prostate cancer providing, therefore, relevant information for patient management.
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 1172.
Abstract 121: Characterization of an extracellular, cell permeable pool of the inhibitor of apoptosis (IAP) protein survivin
Authors: Khan Salma , Slater Jessica M. , Neidigh Jonathan W. , Wall Nathan R. 
Published: February 2011

Abstract
Inhibitor of apoptosis (IAP) and Heat shock proteins (HSPs) provide assistance in protecting cells from the stresses of hypoxia, imbalanced pH, and altered metabolic and redox states commonly found in the microenvironmental mixture of tumor and nontumor cells. HSPs are upregulated, cell-surface displayed and released extracellularly in some types of tumors, a finding that until now was not shared by members of the IAP family. The IAP, Survivin, has been implicated in apoptosis inhibition and the regulation of mitosis in cancer cells. Survivin exists in a number of subcellular locations such as the mitochondria, cytoplasm, nucleus, and most recently, the extracellular space. Our previous work showing that extracellular survivin was able to enhance cellular proliferation, survival and tumor cell invasion provided evidence that survivin might be secreted via an unidentified exocytotic pathway. In the present study, we describe for the first time the exosome-release of survivin to the extracellular space both basally and after proton irradiation-induced stress. To examine whether exosomes contributed to survivin release from cancer cells, exosomes were purified from HeLa cervical carcinoma cells and exosome quantity and survivin content were determined. We demonstrate that although proton irradiation does not influence the exosomal secretory rate, the survivin content of exosomes isolated from HeLa cells treated with a sublethal dose of proton irradiation (3Gy) is significantly higher than control. These data identify a novel secretory pathway by which survivin can be actively released from cells in both the basal and stress-induced state. The quantitation of exosomal survivin from blood or sera may be used to identify the presence of cancer. It may also be feasible to positively impact cancer therapy by targeting exosome-associated protein release, and thus prohibit stress-activated, anti-apoptotic proteins like survivin from impacting the tumor microenvironment and ultimately a patient's response to therapy.
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 121.
Abstract 1213: Cytotoxic T lymphocyte antigen-2 alpha (CTLA-2α) induces apoptosis in lymphoma cells and is regulated by the cAMP/PKA signaling pathway
Authors: Zhang Lingzhi , Hwang Xia , Insel Paul A. 
Published: February 2011

Abstract
The second messenger cAMP promotes apoptosis of lymphoma and leukemia cells but mechanisms that mediate this apoptosis are poorly understood. We thus used wild-type (WT) murine S49 T lymphoma cells and S49 variants that lack PKA and cAMP-promoted responses (kin-) or have normal PKA activity but lack cAMP-promoted-apoptosis (“Deathless”, D-) to examine such mechanisms. Results from DNA microarrays revealed that the largest increase in gene expression induced by 8-CPT-cAMP treatment of WT cells is that of cytotoxic T lymphocyte antigen (CTLA-2α), an inhibitor of cathepsin L-like cysteine proteinases. By contrast, CTLA-2α expression was not increased in kin- S49 cells and only slightly increased in D- S49 cells treated with 8-CPT-cAMP. Real-time PCR and immunoblotting confirmed the prominent cAMP-promoted increase in CTLA-2α expression in WT cells. The β-adrenergic receptor agonist isoproterenol and the adenylyl cyclase activator forskolin also induced CTLA-2α gene expression in WT cells, thus indicating that increased CTLA-2α expression can occur via activation of endogenous activators of the cAMP/PKA signaling pathway. Treatment with an adenoviral construct, Adv-CTLA-2α, induced apoptosis in both WT and D- S49 cells but enhanced cAMP-promoted apoptosis only in WT cells. WT, but not D-, S49 cells treated with 8-CPT-cAMP had increased cathepsin activity. Taken together, these results indicate that the cAMP/PKA pathway up-regulates CTLA-2α expression and based on the contrasting findings obtained with WT vs. D- S49 cells, CTLA-2α may be a key contributor to cAMP/PKA-promoted apoptosis. CTLA-2α and cysteine proteases thus appear to have previously unappreciated roles in apoptosis of lymphoid cells by agents that increase cellular cAMP levels.
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 1213.
Abstract 1218: SMAC modulates gemcitabine-induced apoptosis in head and neck cancer cells
Authors: Sun Quanhong , Zhang Lin , Yu Jian 
Published: February 2011

Abstract
Apoptosis induction is an important anti-tumor mechanism of many conventional chemotherapeutic agents. Biochemical data indicate that SMAC promotes caspase activation by antagonizing IAPs. However, SMAC-knockout mice do not exhibit obvious apoptotic deficiencies in response to a wide range of stimuli. Work for us and others demonstrate that SMAC plays an essential role in apoptosis induced by Nonsteroidal Anti-inflammatory Drug (NSAID), TRAIL or BH3 only proteins in colon cancer cells. In this study we documented a critical role of SMAC in mediating apoptosis induced by chemotherapeutic agent gemcitabine in head and neck squamous cell carcinoma (HNSCC) cells. Using RNA interference, we found that that SMAC mediates gemcitabine-induced apoptosis through the intrinsic/mitochondrial pathway. SMAC Knockdown led to impairment in caspase-3 activation, mitochondrial membrane depolarization and release of cytochrome c. Small-molecule SMAC mimetics at nanomolar concentrations significantly sensitized HNSCC cells to gemcitabine-induced apoptosis, and overcame gemcitabine resistance in SMAC-knockdown cells by restoring caspase-3 activation and cytochrome c release. Furthermore, in xenograft models, SMAC knockdown significantly blocked the therapeutic responses of HNSCC tumors to gemcitabine by inhibiting apoptosis, while SMAC overexpression dramatically enhanced that. Together, these results suggest that SMAC mediates apoptosis in cancer cells, and provide a strong rationale for combining SMAC mimetics with other anticancer agents to treat apoptosis-resistant tumors.
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 1218.