bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2968: Aberrant expression of polycystin-1 in renal cell tumors
Authors: Gogusev Jean , Chretien Yves , Droz Dominique 
Published: February 2011

Abstract
Polycystin-1 (PC1) is a cellular transmembrane protein encoded by the polycystic kidney disease gene (PKD1) prevalently expressed in developing/mature kidney and in autosomal polycystic kidney disease (ADPKD). Limited data are available concerning the PC1 involvement in renal tumorigenesis.
Polycystin-1 expression was evaluated by immunohistochemistry (IHC) in 8 clear cell renal cell carcinomas (RCCs), 7 tubulopapilary cell type tumors, 3 solid RCCs developed in patients with von Hippel-Lindau disease (VHL), one RCC developed in a patient on chronic haemodyalisis and one angyomyolipoma in a patient with Tuberous sclerosis (TS). In parallel, the BIZ cell line derived from a high grade clear cell RCC and the WUR cell line derived from a tubulopapillary type RCC, were used to measure the level of PC1 expression by both immunolabeling and immunoblotting analyses.
Five cases of clear cell type RCCs, and two tubulopapillary cell type RCCs consistently expressed PC1 with a percentage of labeled neoplastic cells ranging between 15% and 65%. Un the VHL disease-associated renal cell carcinoma, both the tumor cells and cystic tissues areas weakly expressed the PC1 protein. In TS-associated angiomyolipoma, the vascular component was PC1 positive, while the tumor cells were scarcely stained. High level of expression of PC1 was confirmed by both IHC and immunoblotting in WUR RCC cells (80% of labeled cells), while BIZ RCC cells exhibited a moderate PC1 staining (30% of labeled cells). Comparatively, in the normal kidney, consistent level of polycystin 1 was detected in distal tubules, collecting duct, glomerular podocytes and vascular smooth muscle cells. The strongest immunoreactivity against PC1 was observed in epithelial cells lining the cystic components in all ADPKD tissues.
In conclusion, the presented data indicate consistent level of expression of the polycystin-1 protein in a number renal cell carcinomas and suggest that PC1 expression is linked to the tumor cell type, being more frequent event in clear cell type RCC.
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 2968.
Abstract 2971: Genomic instability of breast stroma
Authors: Rummel Seth , Ellsworth Rachel E. , Kane Jennifer , Deyarmin Brenda , Hooke Jeffrey A. , Ellsworth Darrell L. , Shriver Craig D. 
Published: February 2011

Abstract
Background: Research in the past decade has demonstrated the importance of the tumor microenvironment in breast cancer development and progression. Allelic imbalance evaluation of tumor and stromal components suggests a limited number of alterations in the tumor may lead to cellular transformation while tumor behavior may be driven by molecular changes in the surrounding stroma. Recent studies evaluating copy number changes in frozen stromal tissue, however, found no chromosomal alterations and suggested that earlier studies represent artifacts from the use of archive tissues.
Methods: High-quality flash-frozen specimens were collected from breast quadrants from 14 patients undergoing mastectomy; patient characteristics ranged from prophylactic mastectomy to stage IV breast cancer. DNA was isolated (Gentra) from benign tissue sections and hybridized to GeneChip Human Mapping 250K arrays (Affymetrix). Genomic DNA from peripheral blood for each patient was genotyped to assess copy number variation (CNV) by paired analysis. CNVs were identified using Genome Console 3.0.2 (Affymetrix) with a minimum genomic size/fragment of 500 Kb and a minimum of 50 markers/segment.
Results: Copy number changes ranging in size from 586-5061 kb were detected in 50% (7/14) patients in at least one quadrant, with a single patient having copy number changes present in each quadrant. 21% of quadrants (12/57) showed detectable copy number changes affecting 1 - 18 chromosomal arms. Copy number changes were detected not only in stroma from diseased breasts, but in prophylactic mastectomies, as well. Copy number changes were observed in all quadrants irrespective of tumor location. While copy number alterations on chromosomes 1q21, 2p21, 12p13, 14q12 and 18q12 were shared between patients, no patient had the same patterns of CNVs across all quadrants.
Conclusions: Chromosomal alterations were detected in high-quality frozen breast stroma specimens utilizing genome-wide SNP array data, supporting earlier claims that breast stroma may be genetically unstable. Half of the patients in this study demonstrated copy number alterations in breast stroma distant from the tumor, suggesting that for a subgroup of breast cancer patients, widespread chromosomal instability may increase risk of recurrence.
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 2971.
Abstract 2975: Two putative founder MSH6 mutations associated with inherited cancer susceptibility in Ashkenazi Jewish population
Authors: Schwenter Frank , Raskin Leon , Freytsis Marina , Bogomolniy Faina , Aronson Melyssa , Rennert Gad , Gallinger Steven , Levine Douglas A. , Tischkowitz Marc , Gruber Stephen B. , Foulkes William 
Published: February 2011

Abstract
Background
Inherited mutations in DNA mismatch-repair genes are the cause of several cancers associated with Lynch syndrome. The most common mutations affect MLH1 and MSH2 genes, while the MSH6 gene is less commonly involved. Furthermore, MSH6 mutations have been observed to result in an attenuated form of the syndrome. We report here case-control studies of two putative MSH6 founder mutations in the Ashkenazi Jewish (AJ) population.
Methods
Case-control studies were performed using DNA extracted from the blood of individuals of AJ descent presenting cancers compatible with Lynch syndrome and AJ individuals unaffected by cancer as controls. The DNA samples were screened for the presence of the two mutations in exon 9. The frequency of the mutations and the range of malignancies were analyzed.
Results
Among 2104 population-based AJ colorectal cancer cases (CRC), 8 carried a 4 bp duplication mutation, c.3984_3987dupl (0.38%), and 3 carried a 4 bp deletion mutation, c.3959_3962del (0.14%), in the exon 9 of the MSH6 gene. In comparison, 1 duplication (0.06%) and no deletions were observed in 1813 control individuals. The odds ratio for the c.3984_3987dupl and the c.3959_3962del in this population are OR = 8.64 (exact 95%CI 1.23-375, Fisher's exact test two-sided P = 0.04) and OR = NA, P = 0.25, respectively. Notably, the one control found to carry the duplication was, during the course of follow-up, diagnosed with both cecal and endometrial cancer. In a hospital-based series of 78 CRC, one individual carried the deletion, but no duplications were seen. Among 136 hospital-based AJ endometrial cancer cases, 2 carried the duplication, leading to an OR of 27.0 (95%CI: 1.39-1596, P = 0.014) when compared with the 1813 controls. In a series of 61 hospital-based AJ pancreas cancer cases, no duplication carriers were seen, but 1 individual carried the deletion (OR NA, P = 0.033). Notably, this individual developed 3 independent primary cancers - pancreas cancer, CRC and rhabdomyosarcoma. Testing for microsatellite instability and loss of MSH6 protein is in progress in these samples.
Conclusion
These rare, probable founder, MSH6 truncating mutations reported here are of great importance for the screening, genetic counseling and follow-up of Ashkenazi Jewish families presenting malignant tumors compatible with Lynch syndrome.
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 2975.
Abstract 2977: LSD1 is Required for Chromosome Segregation during Mitosis
Authors: Lv Shuang , Bu Wenjuan , Jiao Hong , Liu Bo , Zhu Lin , Zhao Hongchang , Liao Ji , Li Jing , Xu Xingzhi 
Published: February 2011

Abstract
Dynamic methylation/demethylation of histones and non-histone proteins occurs during the cell cycle. Lysine-specific demethylase 1 (LSD1) exhibits diverse transcriptional activities through catalyzing demethylation of mono- and di-methylated histone H3 on lysine 4 (H3K4) and lysine 9 (H3K9). We show here that inhibition of LSD1 expression by siRNA leads to abnormal chromosomal segregation in unperturbed mitosis and abnormal centrosome duplication, and is associated with decreased protein levels of MAD2 and BUBR1. LSD1 positively regulates the BUBR1 and MAD2 promoter activity and maintains local monomethylation status of H3K9, which is a repressive histone mark for gene transcription. Expression of exogenous BUBR1 and MAD2 in LSD1-depleted cells partially rescues the defect of chromosome segregation. Our results suggest that LSD1 plays a role in chromosomal segregation during mitosis partially through transcriptional regulation of BUBR1 and MAD2.
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 2977.
Abstract 2978: Nucleotide excision repair contributes to hexavalent chromium-induced double strand breaks and chromosomal damage
Authors: Savery Laura C. , O'Brien Travis J. , Holmes Amie L. , Wise John P. , Patierno Steven R. 
Published: February 2011

Abstract
Certain hexavalent chromium (Cr(VI)) compounds are known human lung carcinogens. Cr(VI) causes several types of DNA damage including bulky adducts and crosslinks. Cr(VI)-induced tumors exhibit chromosomal instability (CIN), however, very little is known about mechanisms of these effects and the role that DNA repair plays in this process. Nucleotide excision repair (NER) is known to be involved in the repair of bulky DNA damage. Unrepaired or misrepaired lesions can lead to chromosomal aberrations (CAs). We investigated the role of NER leading to CAs using Chinese hamster ovary (CHO) parental (AA8) and NER-deficient cells (UV-5). We found that UV-5 cells displayed attenuated Cr(VI)-induced chromosome damage. In general, DNA lesions need to be converted to DNA double strand breaks (DSBs) in order to give rise to CAs. Therefore, we used the neutral Comet assay to measure the induction and repair of DSBs after Cr(VI)-induced damage. We found that both parental and NER-deficient cell lines displayed low levels of DSBs immediately after Cr(VI) treatment. Interestingly, DSB formation peaked after a 24h recovery period, and NER-deficient cells exhibited lower overall levels of DSBs than repair-proficient cells. All damage in both cell lines was repaired by 48h following Cr(VI) exposure. Taken together, our results suggest that Cr(VI)-induced DSBs are not directly formed by Cr(VI) exposure. Instead, these lesions develop as a consequence of repair of, or replication past, Cr(VI)-induced lesions. Importantly, our data suggests that NER contributes to Cr(VI)-induced genomic instability.
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 2978.
Abstract 298: Mutant PIK3CA increases the expression of individual tubulin isoforms and promotes resistance to anti-mitotic chemotherapy drugs
Authors: Wallin Jeffrey J. , Guan Jane , Xiao Yang , O'Brien Tom , Belvin Marcia , Friedman Lori S. 
Published: February 2011

Abstract
Resistance to many anti-cancer agents has been attributed to increased PI3K/PTEN pathway signaling. Hence, inhibitors of the pathway have potential utility in combination with these therapies. To investigate chemotherapy drug sensitivities downstream of mutant PIK3CA in a controlled and patient-relevant context we utilized human non-tumorigenic MCF10A parental and isogenic knock-in cell lines that harbor a common activating PIK3CA kinase domain mutation (H1047R). We found the mutant cells to be least sensitive to anti-mitotic drugs, but the resistance could be overcome in combination with GDC-0941, a Class I PI3K inhibitor currently being evaluated in clinical trials. To understand the mechanism of resistance we analyzed microarray data for expression of known anti-mitotic resistance genes. We found that a subset of tubulin isoforms were increased with PI3K pathway signaling, but were reduced with GDC-0941 treatment. The changes in mRNA expression were confirmed at the protein level and were extended to additional cell lines. RNAi knockdown of TUBB2, the isoform we found to be most influenced by PI3K pathway signaling, increased the sensitivity of both parental and H1047R clones to anti-mitotic drugs, but did not influence GDC-0941 potency. Thus, reduced expression of the target increases the potency of the anti-mitotic drug. Overall, these findings suggest a mechanism of action for anti-mitotic drugs in combination with inhibitors of PI3K.
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 298.
Abstract 2981: Regulation of Snail by DDX3 and ATM in response to DNA damage
Authors: Sun Mianen , Zhou Tong , Gillespie Yancey , Xu Bo , Jope Richard 
Published: February 2011

Abstract
Epithelial-mesenchymal transition (EMT) is the initial step for cancer invasion and metastasis. The hallmark of EMT is the loss of expression of E-cadherin, a cell-cell adhesion protein, allowing cancer cells to gain mobility leaving the site of primary tumor to invade adjacent tissues. Snail, as a transcription repressor, binds to the E-boxes of E-cadherin and then inhibits E-cadherin expression. Thus, Snail is essential to trigger EMT during tumor progression and it has been implicated in the acquisition of invasive growth phenotype of tumors. There is a strong correlation of Snail over-expression with tumor invasion and metastasis. However, how Snail expression is regulated is not fully known. Here we report that Snail is regulated by DDX3, a DEAD box protein family member which contributes to cancer progression. Knock-down of DDX3 by shRNA reduces the basal level of Snail, and this is associated with reduced cell proliferation and migration. Snail protein and mRNA levels are increased in the presence of the HDAC inhibitors sodium butyrate or trichostatin A, and the increases are attenuated in cells with DDX3 knocked down. Treatment of cells with a DNA damaging agent camptothecin also enhances Snail protein levels in a DDX3 dependent manner. Therefore we conclude that DDX3 is required for the basal level and the increase in Snail induced by HDAC inhibitors or camptothecin, indicating that this action of DDX3 may contribute to its promotion of the progression of some cancers. This conclusion is supported by our clinical investigations that analysis of 31 glioblastoma patient samples has revealed a strong correlation between the levels of DDX3 and Snail. Snail is a phosphor-protein, and kinases responsible for phosphorylation include Pak1 and GSK3-β. We also find Pak-1 and GSK-3 independent Snail phosphorylation in response to DNA damage. Further we find that inhibition of the activity of the ATM kinase, a critical element in DNA damage responses, eliminated DNA damage-induced Snail stabilization. Taken together, these observations have highlighted a comprehensive signaling network regulating Snail in response to DNA damage and indicated a critical role of optimal DNA damage responses in tumor invasion and metastasis.
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 2981.
Abstract 2983: Che-1 promotes tumor cell survival by sustaining mutant p53 transcription and inhibiting DNA damage response activation
Authors: Bruno Tiziana , Santis Agata De , Bossi Gianluca , Agostino Silvia Di , Sorino Cristina , Nicola Francesca De , Iezzi Simona , Franchitto Annapaola , Benassi Barbara , Floridi Aristide , Bellacosa Alfonso , Passananti Claudio , Blandino Giovanni , Fanciulli Maurizio 
Published: February 2011

Abstract
Che-1 is a RNA polymerase II binding protein involved in the regulation of gene transcription, and in response to DNA damage promotes p53 transcription. In this study, we investigated whether Che-1 regulates mutant p53 expression. We found that Che-1 is required for sustaining mutant p53 expression in several cancer cell lines, and Che-1 depletion by siRNA induces apoptosis both in vitro and in vivo. Notably, loss of Che-1 activates DNA damage checkpoint response and induces transactivation of p73. Therefore, these findings suggest a new therapeutic approach that allowing simultaneous modulation of p73 and mutant p53 levels might be used to target the large fraction of human tumors harboring p53 mutations.
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 2983.
Abstract 2985: DNA-damage related histone marks can distinguish the anti-tumor effects of established and novel histone deacetylase inhibitors in ovarian cancer cells
Authors: Wilson Andrew J. , Holson Ed , Bhaskara Srividya , Carlise Jahred , Schreiber Stuart L. , Hiebert Scott W. , Khabele Dineo 
Published: February 2011

Abstract
The majority of epithelial ovarian carcinomas harbor molecular alterations in DNA-damage response genes. Epithelial ovarian cancers are surprisingly sensitive to DNA-damaging platinum-based (cisplatin or carboplatin) chemotherapy, suggesting that the dependencies of ovarian cancers on impaired DNA-damage response pathways can be harnessed for therapeutic purposes. Our group and others have shown that histone deacetylase (HDAC) inhibitors are promising anti-tumor agents, particularly when combined with DNA-damaging drugs in ovarian cancer cells. In this study, H2AX phosphorylation (pH2Ax), a known histone mark of DNA damage and other histone marks related to DNA damage and repair pathways, including the newly recognized acetylated lysine K56 on histone 3 (H3K56ac) were used to distinguish the biological effects of a unique and diverse panel of clinically utilized and novel HDAC inhibitors. Ovarian cancer cell lines with diverse molecular alterations, including mutations in p53, Brca1, Akt, Ras, and overexpression of MDR1, were utilized in these screens. The HDAC inhibitors that induced the highest levels of pH2Ax produced the greatest anti-tumor effects (growth inhibition and apoptosis). Furthermore, a screen of DNA-damage response histone marks led to the selection of novel HDAC inhibitors that exerted synergistic anti-tumor effects when combined with cisplatin and other DNA-damaging drugs. Taken together, our results support a role of HDAC inhibitors in the treatment of ovarian cancer and suggest that pH2Ax is a potential surrogate biomarker of the efficacy of HDAC inhibitor combination therapy with DNA-damaging agents.
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 2985.
Abstract 2988: A PP6-phosphatase complex is required for homology-directed repair of DNA double-strand breaks
Authors: Zhong Jianing , Liao Ji , Yao Lu , Liu Jinping , Stark Jeremy , Lees-Miller Susan , Xie Yuntao , Xu Xingzhi 
Published: February 2011

Abstract
DNA double-strand breaks (DSBs) are among the most lethal lesions associated with genome stability which, when destabilized, predisposes organs to cancers. DSBs are primarily fixed either with little fidelity by non-homologous end joining (NHEJ) repair or with high fidelity by homology-directed repair (HDR). The phosphorylated form of H2AX on serine 139 (g-H2AX) is a marker of DSBs. It is dephosphorylated by PP2A-like protein phosphatases (PP2A, PP4, and PP6). Here, we identify three novel PP6 subunits. Several PP6c (the catalytic subunit of PP6)-containing heterotrimeric complexes show phosphatase activities against g-H2AX in the in vitro phosphatase assays using bacterially-produced proteins, providing direct evidence that the PP6 holoenzyme is a PP6c-containing heterotrimeric complex. Furthermore, depletion of PP6c, PP6R2, or MyPT1 leads to defective HDR, and expression of phosphatase-inactive PP6c fails to rescue this defect. Chromatin immunoprecipitation assays demonstrated that PP6c is recruited to the region adjacent to the DSB sites. Expression of PP6R2, but not PP6c or MyPT1, is associated with improved overall survival in patients with breast cancer at five years (n=100, p=0.038). Taken together, our results suggest that the PP6-PP6R2-MyPT1 complex is required for HDR and PP6R2 is a potential therapeutic target.
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 2988.