bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1166: PTEN loss and ERG over-expression as prognostic biomarkers in prostate cancer and identification of downstream biomarkers with potential therapeutic value
Authors: Williams Julia L. , Yoshimoto Maisa , Nuin Paulo , Greer Peter A. , Squire Jeremy A. 
Published: August 2012

Abstract
Genomic deletion of the PTEN tumor suppressor gene and formation of the TMPRSS2:ERG gene fusion are the two most recurrent genomic aberrations in prostate cancer. The lipid phosphatase activity of PTEN negatively regulates the PI3Kinase-AKT signaling pathway, which controls numerous downstream targets such as cell cycle checkpoints, DNA damage repair with maintenance of chromosomal stability and integrity. ERG is a member of the ETS transcription factor family, whose members are implicated in numerous cellular processes including membrane remodelling, angiogenesis, differentiation, proliferation, and tumourigenesis. Emerging evidence suggests that formation of the fusion gene may promote prostatic tumourigenesis, progression, and invasive disease by elevating motility and invasiveness. The simultaneous manifestation of both PTEN loss and TMPRSS2:ERG fusion is associated with poor prognosis. This study is addressing pathways downstream of PTEN and effectors of ERG over-expression to identify additional biomarkers of prognostic and therapeutic potential. In silico genomic copy number analyses demonstrated that patient samples harboring a genomic deletion of PTEN have a greater number of genomic aberrations, in keeping with the model that loss of PTEN leads to heightened genomic instability. Mining of publically available gene expression datasets have been performed to further examine signalling pathway aberrations specific to each rearrangement. PTEN loss and ERG over-expression are being modeled in the histologically normal prostate epithelial cell line RWPE-1 using shRNA knockdown or transgene directed ectopic over-expression, respectively. Biochemical, proliferation, migration and invasion assays will be performed to determine if knockdown of PTEN leads to the expected AKT activation and increased proliferation; whereas over-expression of ERG in RWPE-1 cells correlates with heightened motility and invasive potential. Gene expression microarray profiling will also be carried out for each derivative RWPE-1 cell line using the Agilent SurePrint G3 Human Exon microarrays. This cell model system will be used to validate transcriptional changes associated with PTEN loss and ERG over-expression in prostate cancer gene expression datasets and identify potential novel downstream therapeutic targets and predictive biomarkers.
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 1166. doi:1538-7445.AM2012-1166
Abstract 1168: Identification of CNA signatures in prostate cancer: Narrowing chromosome regions related with occurrence, prognosis and recurrence after treatment
Authors: Rodrigues Tatiane C. , Carvalho Felipe , Krepischi Ana C. V. , Verjovski-Almeida Sergio , Rosenberg Carla 
Published: August 2012

Abstract
Prostate cancer is the most common cancer in males and, despite its high incidence, only limited data are available on which genes or chromosome regions are specifically involved in its initiation and progression. We studied 72 prostate tumor samples by array-CGH, using a platform containing 60.000 oligonucleotides spread over the whole genome (60K Agilent Technologies). No chromosome alterations (CNA) were detected in 13 samples. The array-CGH profiles of the remaining samples showed losses at 8p and gains on 8q, often with narrow peaks of amplification, in ∼50% of the tumors. Additionally, losses at 6q, 13q and 16q were observed in ∼25% of the samples. Although these results are in general agreement with the location of alterations described earlier, the altered chromosome segments are often several megabases long. Mapping of minimum regions altered in several tumors, or pronounced copy number changes in smaller segments, permits a more precise definition of the relevant chromosome regions that are relevant for tumor development and progression. Current prognostic variables include prostatic specific antigen (PSA), the pathologically defined Gleason score (GS) and T-category (of the TNM staging). There is a great heterogeneity within the intermediate risk group and further genetic markers are needed to refine disease diagnosis and prognosis. So, we analyzed the copy number alteration signatures for the intermediate risk group, Gleason 7. In the comparison between samples related as GS 6 versus GS 7, we found that losses on 5q21.1 and gains on 7q11.21 are more frequent in GS 7. In other hand, losses on 22q13.33 are more frequent in GS 7 than in GS 8 and 9, while losses on 6q21 and 18q21 are correlated with GS 8 and 9. Additionally, we have medical follow-up of only 46 of the 72 samples. Fifteen of these patients had present recurrence after treatment. We analyzed this group versus the group with no recurrence. Losses at 2p21, 6q12, 7q36.3 and 16q13 are more frequent in the group of patients in which there is recurrence of the tumor. This suggests that these alterations could also be hallmarks for recurrence. Further studies with array-CGH of prostate tumors samples will ultimately lead to defining much smaller regions of overlap than at present, which in turn will indicate which specific individual genes and/or combinations of genes are the real “drivers” in prostate cancer or could act as hallmarks for prognosis and recurrence.
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 1168. doi:1538-7445.AM2012-1168
Abstract 1169: Non-canonical functions of Mdm2 isoforms in estrogen influenced breast cancer cells with wild-type or mutant p53
Authors: Bargonetti Jill , Okoro Danielle , Kundu Nandini , Brekman Angelika , Gao Chong , Rosso Melissa , Polotskaia Alla 
Published: August 2012

Abstract
Estrogen receptor positive breast cancers often have high levels of Mdm2. We investigated if estrogen signaling in breast cancers occurred through an Mdm2 mediated pathway. We examined the effect of long-term 17β-estradiol (E2) treatment in ERα positive breast cancer cell lines that contain wild-type p53 (MCF-7) and mutant p53 (T-47D). These cell lines also contain the mdm2 SNP at position 309, which increases the expression of Mdm2 by Sp1 driven transcription. In both these cell lines, we observed that E2 treatment dramatically increased the amount of Mdm2 without decreasing the corresponding wild-type or mutant p53. Surprising the amount of p53 protein in both cell lines increased with E2 treatment. We engineered miR30-based inducible mdm2 knockdown cell lines of MCF-7 and T-47D to evaluate to impact of Mdm2 on their cancer cell phenotypes. The down-regulation of Mdm2 in MCF-7.shmdm2 and T-47D.shmdm2 inhibited cell proliferation in 2D culture and in 3D laminin-rich matri-gel. Knockdown of Mdm2 did not cause an increase in p53 protein. These data suggest a p53-independent signal transduction pathway for Mdm2-mediated activation of proliferation. Alternative spliced mdm2 transcripts have been observed in many cancers including breast, but no endogenous protein isoforms from the spliced isoforms have been described. We asked if the spliced variant Mdm2-C transcript (that lacks most of the N-terminal p53 binding domain) expressed endogenous protein in these breast cancer cell lines. We created an Mdm2-C specific antibody using a synthetic peptide to the splice junction of exons four and ten (C4-10) to detect the protein. We validated the C4-10 antibody using in vitro translated Mdm2 compared to Mdm2-C. High expression of Mdm2-C occurred in the G/G mdm2 SNP309 ER+ breast cancer cell line T-47D, but only a slight increase was detected in the presence of E2. Additionally, Mdm2-C was found in nucleolar and cytoplasmic foci before and after estrogen treatment, while the mutant p53 was predominantly nuclear. We report the first identification of endogenous tumor-associated Mdm2-C protein in breast cancer. We suggest that Mdm2 and its isoforms work through non-canonical pathways to transform estrogen influenced breast cancers through molecular pathways that remain to be elucidated. Acknowledgements: This work was supported by Breast Cancer Research Foundation to J.B. and NSF grant to JB MCB-0744316. D.O. was also partially supported by a CUNY Graduate Center Magnet Award. Special thanks to Gerard Evan for help with immunogen peptide design.
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 1169. doi:1538-7445.AM2012-1169
Abstract 117: The processed pseudogene POU5F1P1in 8q24 is expressed in tumor and shows oncogenicity
Authors: Fang Jun 
Published: August 2012

Abstract
Genome-wide association studies (GWAS) have identified a segment of approximately 1 Mb of 8q24 as a multi-cancer cancer susceptibility region. The region is flanked by two genes, FAM84B and MYC, the latter an established oncogene. Within this region of 8q24, there is a processed pseudogene, POU5F1P1. We have re-sequenced the exon regions of wild type POU5F1 on chromosome 6 and its six counterpart pseudogenes on chromosomes 1, 3, 8, 10 and 12, and identified sequence variants unique to POU5F1P1 for which we have developed and confirmed analysis of expression of the POU5F1P1 transcript on 8q24. The homolog between wild type POU5F1 and pseudogene POU5F1P1 is about 97%. By using TaqMan DNA copy number variation assays, we identified uncommon copy number variants across this region. However, the DNA copy number variation does not contribute to differences in expression of POU5F1P1. Expression of POU5F1P1 was confirmed in a subset of the NCI60 panel using quantitative TaqMan real-time PCR assays in cell lines of colon, ovarian and breast cancers. Both POU5F1 and POU5F1P1were further evaluated in 14 colon cancer cell lines of which two, DLD-1 and KM12, expressed POU5F1P1 but no wild type POU5F1. Using shRNA technology (two constructs for each target), we knocked down POU5F1P1 expression in DLD-1 and KM12, which lead to reduction in the growth rate and anchorage-independent growth of colon cancer cells. Our results suggest that the processed pseudogene, POU5F1P1 is expressed in cell lines and colon cancer tissues. Moreover, preliminary studies suggest that its function could be related to oncogenic activity, though further studies are needed to verify this observation.
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 117. doi:1538-7445.AM2012-117
Abstract 1172: Prodigiosin and its structural analogue rescue deficient p53 pathway signaling and anti-tumor effects via p73 upregulation in p53 mutant and null colorectal cancer cells
Authors: Hong Bo , Dicker David T. , Kopelovich Levy , El-Deiry Wafik S. 
Published: August 2012

Abstract
The tumor suppressor p53 gene is mutated in over 50% of human cancers, and this is associated with resistance to radiotherapy and chemotherapy as well as tumor progression. Therefore, p53 pathway functional reactivation in p53-deficient cancers is an attractive strategy for cancer therapy and may address an unmet need in the clinic for progressive therapy-refractory human tumors. We previously showed that Prodigiosin and its structure analogue can reactivate the p53 pathway in p53 mutant and null colorectal cancer cells (Hong et al. AACR 2011, abstract 607). Here, we examined the mechanism of p53 pathway reactivation by Prodigiosin and its structural analogue in colorectal cancer cells. p73, a p53 family protein, shares a high degree of sequence homology with p53 and regulates the expression of similar genes by binding to p53 responsive elements within gene promoters and performs similar functions to p53. However, unlike p53, p73 is not a target for mutational inactivation in human cancer. In the study, we hypothesized that Prodigiosin and its structural analogue induce p73 expression to activate the p53 pathway and further induce cellular apoptosis in p53-deficient cancer cells. We showed that Prodigiosin and its structural analogue induced p73 expression in p53 mutant SW480 and p53−/− HCT116 cells. We also showed that the induction of p53-responsive transcriptional activities by Prodigiosin and its structural analogue was reduced in SW480 cells with p73 stable knockdown, as compared with parental SW480 cells. Western blot analysis indicated that the induction of a p53 target protein DR5 by Prodigiosin and its structural analogue was decreased in SW480 cells with p73 stable knockdown, as compared with parental SW480 cells. The sub-G1 analysis demonstrated that Prodigiosin and its structural analogue induced less apoptosis in SW480 cells with p73 stable knockdown than parental SW480 cells. Together, these findings indicate that p73 upregulation is involved in the mechanism of p53 pathway activation and apoptotic induction by Prodigiosin and its structural analogue. The study suggests that p73 induction may be a useful alternative way to reactivate p53 pathway in p53 mutant and null cancer cells and provides important mechanistic insights into the activity of a potent p53 pathway function restoring small molecule that is a candidate therapeutic for human cancer. This work was supported by the NCI Developmental Therapeutics Program through NCI Contract N01-CN-43302.
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 1172. doi:1538-7445.AM2012-1172
Abstract 1174: ASPP2: Tumor suppression through the control of polarity and proliferation
Authors: Lu Xin 
Published: August 2012

Abstract
Cell polarity and proliferation are processes that play key roles in development. Loss of cell polarity and increased cellular proliferation are hallmarks of human cancer. The identification of molecules that are involved in the control of these processes is, therefore, important for our better understanding of tumor development and progression. p53 was recently found to be important in controlling the mammary epithelial stem cell pool. We have recently shown that ASPP2, a regulator of p53 and binding partner of many other proteins including YAP, is an important player in the regulation of cell polarity due to its ability to bind and regulate Par-3. Interestingly, ASPP2 is also able to directly regulate cell proliferation by affecting the activity of cyclin D1, by inhibiting the nuclear localisation of SUMO-modified cyclin D1. As ASPP2 is a haploinsufficient tumor suppressor, these findings identify ASPP2 as a unique regulator of cell polarity: able to influence cell polarity on the one hand and the cell cycle machinery on the other. ASPP2's interactions with p53, YAP and others, along with its potential role in controlling cell migration and EMT will be discussed. References Samuels-Lev Y, O'Connor DJ, Bergamaschi et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol Cell. 2001 Oct;8(4):781-94. Vives V, Su J, Zhong S, Ratnayaka I, Slee E, Goldin R, Lu X. ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth. Genes Dev. 2006 May 15;20(10):1262-7. Sottocornola R, Royer C, Vives V et al. ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development. Dev Cell. 2010 Jul 20;19(1):126-37. Epub 2010 Jul 8. Wang XD, Lapi E, Sullivan A, Ratnayaka I, Goldin R, Hay R, Lu X. SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence. Cell Death Differ. 2011 Feb;18(2):304-14. Epub 2010 Aug 27.
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 1174. doi:1538-7445.AM2012-1174
Abstract 1175: The tumor-associated p53 R172H mutation does not display gain-of-function properties in hepatocellular carcinoma
Authors: Ahronian Leanne G. , Lewis Brian C. 
Published: August 2012

Abstract
Hepatocellular carcinoma is a highly deadly malignancy, accounting for approximately 600,000 deaths worldwide every year. A common genetic change in HCC, present in 30% of cases, is mutation of the p53 tumor suppressor gene. p53R175H (corresponding to R172H in mice) is a hotspot for mutation that demonstrates “prometastatic” gain-of-function in pancreatic cancer. Since the frequency of p53 mutation increases with tumor grade in HCC, we hypothesized that p53R172H is a gain-of-function mutation in HCC that contributes to an increase in metastasis and a decrease in tumor-free survival. To study the role of p53 mutation in HCC, we used the RCAS-TVA mouse model. Albumin-TVA, p53LSL-R172H/fl, Albumin-cre mice were crossed to Albumin-TVA, p53fl/fl, Albumin-cre mice to generate litters in which half of the progeny are p53fl/fl and half are p53R172H/fl. Injection of these litters with DF1 chicken fibroblasts producing RCAS viruses encoding the mouse polyoma virus middle T antigen (PyMT), resulted in specific infection and expression of PyMT in the liver. We found that p53R172H/fl mice did not have increased tumor incidence, nor did they display increased rates of metastasis, relative to p53fl/fl mice, suggesting that mutant p53 does not display gain-of-function properties during HCC development in vivo. Interestingly, while shRNA-mediated knockdown of p53 in R172H expressing HCC cell lines resulted in decreased cell migration, suggestive of gain-of-function properties, analysis of a panel of HCC cell lines from p53 null and R172H expressing tumors found no differences in anchorage-independent growth and cell migration between the two groups. Thus, although p53R172H expressing HCC cells depend on this mutant for their transformation, p53 mutant cells and tumors do not have enhanced properties relative to p53 null HCC cells and tumors. These data suggest that important pathway(s) impacted by mutant p53 are inhibited by alternate mechanisms in p53 null cells resulting in equivalent phenotypes. Interestingly, cell lines derived from HCCs with conditional p53 deletion exhibit decreased levels of a p63 isoform compared to cells from p53R172H mice. Since p53 mutants have been previously shown to bind and inhibit p63, reduced p63 expression in p53 deficient HCC cells may explain this observation. Elucidation of the role of p63 in regulating HCC migration and metastasis is currently underway.
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 1175. doi:1538-7445.AM2012-1175
Abstract 1179: 15-PGDH inhibits cholangiocarcinogenesis through the induction of TAp63
Authors: Lu Dongdong , Han Chang , Wu Tong 
Published: August 2012

Abstract
NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is responsible for the catabolism of prostaglandins in a variety of cell types such as inflammation an dtumorigenesis. In this study we showed that forced overexpression of 15-PGDH in human cholangiocarcinoma cells (CCLP1) suppressed tumor cell growth, invasion and clonogenic formation capacity. In contrast, 15-PGDH knockdown in CCLP1 cells enhanced tumor cell growth, invasion and clonogenic formation. Flow cytometry analysis revealed that 15-PGDH overexpression induced cell cycle arrest at G1/S checkpoint. When implanted into SCID mice, 15-PGDH overexpressed CCLP1 cells formed smaller xenograft tumors, whereas 15-PGDH-depleted cells formed larger xenograft tumors when compared with each of the corresponding controls (p&lt;0.01). In addition, intratumoral injection of an adenoviral vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited the growth of cholangiocarcinoima in SCID mice. Western blot analysis showed that 15-PGDH induced the expression of TAp63, a key tumor suppressive gene. Furthermore, 15-PGDH induced the phosphorylation of Smad2/3 and enhanced the interaction between p53 and pSmad2/3 in CCLP1 cells; the pSmad2/3 and p53 binding complex appeared to play a key role for the induction of TAp63 expression. Taken together, our data suggest that 15-PGDH inhibits cholangiocarcinoma growth and this effect is at least in part through pSmad2/3 and p53-mediated induction of TAp63.
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 1179. doi:1538-7445.AM2012-1179
Abstract 1180: Modulation of p73 isoform expression regulates aggressive behavior in NHL cell line model with 1p36 chromosomal disruption
Authors: Hassan Hesham M. , Varney Michelle L. , Joshi Shantaram S. , Singh Rakesh K. , Dave Bhavana J. 
Published: August 2012

Abstract
Abnormalities of chromosome 1p36 locus are frequently detected in non Hodgkin lymphoma (NHL) and are associated with aggressive clinical behavior. TP73, a gene at 1p36 locus, is a member of the p53 tumor suppressor gene family, and regulates many important cellular pathways. TP73 gene function is controlled by a balance between two isoforms with opposing functions, the full length TAp73 protein (pro-apoptotic) and the NH2-terminally truncated ΔNp73 protein (anti-apoptotic through antagonizing both TAp73 and p53). Our previous work on diagnostic specimens of NHL cases had shown a differential ΔNp73 up-regulation and increase in ΔNp73:TAp73 expression ratio among NHL cases with 1p36 chromosomal disruption as compared to NHL cases without 1p36 disruption, which correlates with decreased apoptosis, increased cellular proliferation and increased angiogenesis. We hypothesized that modulated expression of the p73 isoforms will alter the aggressive behavior of a NHL cell line containing 1p36 disruption. We used a NHL cell line (Granta-519) that has 1p36 disruption as a model. Granta-519 cells express higher levels of ΔNp73 isoform similar to what was observed in NHL cases with 1p36 abnormality. Next, we stably transfected Granta-519 with a TAp73 mammalian expression vector to modulate the ΔNp73:TAp73 ratio. Cell cycle analysis showed an increase in the percentage of G1 cells and decrease in the percentage of S and G2 cells in TAp73-trasnfected Granta-519 cells as compared to control vector-transfected cells. Serum deprivation significantly inhibited the growth of Granta-519-TAp73- cells as compared to control vector-transfected cells. Moreover, reconstitution of TAp73 expression in Granta-519 cells significantly enhanced their response to Doxorubicin. Together, these results provide an insight on modulation of ΔNp73:TAp73 as a novel therapeutic target in NHL with 1p36 abnormalities.
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 1180. doi:1538-7445.AM2012-1180