bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2388: Deciphering the role of APE1 protein variants in disease etiology
Authors: Illuzzi Jennifer , Harris Nicole A. , Manvilla Brittney A. , Kim Daemyung , Li Mengxia , Drohat Alexander C. , Wilson David M. 
Published: May 2015

Abstract
Base excision repair (BER) is necessary for removal of DNA damage that has occurred from spontaneous decomposition, alkylation and oxidation. Defects in BER have been associated with cancer predisposition, neurodegeneration and premature aging. BER is initiated by a damage-specific DNA glycosylase that excises the damaged base, creating an apurinic/apyrimidinic (AP) site. The AP site is recognized by the multifunctional AP endonuclease 1 (APE1), which cleaves the phosphodiester backbone, producing a DNA strand break. DNA polymerase beta incorporates the correct nucleotide, and BER is completed via ligation by a protein complex of Ligase III and XRCC1. Like many BER proteins, APE1 is essential for survival, as deletion of both alleles in mice leads to embryonic lethality. We are pursuing the hypothesis that more mild reductions in APE1 activity will contribute to disease risk and development. To address this issue, we have engaged two strategies: (1) identification and characterization of APE1 missense mutations and (2) design and characterization of genetically-altered mutant human cell lines. In our first study, we have characterized eight APE1 variants found within the population or identified in endometrial cancer. Our studies reveal that while most of these proteins are normal for protein stability, biochemical activities, and intracellular localization, the endometrial cancer-associated variant Arg237Cys has decreased 3′-functions and AP-DNA binding. In our second study, we have created a heterozygous knockout HCT116 cell line, in which we have deleted one allele of APE1. The heterozygous knockout cells show a loss in AP endonuclease activity and are hypersensitive to DNA damaging drugs. Current cellular strategies are determining the essential nature of APE1 activity in HCT116 and other cell lines
Citation Format: Jennifer Illuzzi, Nicole A. Harris, Brittney A. Manvilla, Daemyung Kim, Mengxia Li, Alexander C. Drohat, David M. Wilson. Deciphering the role of APE1 protein variants in disease etiology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2388. doi:10.1158/1538-7445.AM2014-2388
Abstract 2389: PTEN localizes to the nucleus and interacts with Rad52 in response to DNA damage
Authors: Choi Byeong Hyeok , Dai Wei 
Published: May 2015

Abstract
PTEN is a tumor suppressor with a dual phosphatase activity. Mutations of PTEN gene has been associated with many sporadic cancers and heritable neoplastic syndromes. PTEN also exhibits nuclear localization. However, the exact function of nuclear PTEN remains unclear. Here we show that PTEN exhibits a time-dependent nuclear translocation after DNA damage, co-localizing with DNA damage foci on chromatin, and that the nuclear translocation of PTEN is closely associated with its phosphorylation on S366/T370. Deletional analysis reveals that C2 domain of PTEN is responsible for its nuclear translocation after exposure to genotoxin. Both casein kinase 2 and GSK3β are involved in the phosphorylation of S366/T370, as well as PTEN's association with chromatin during DNA damage response. Significantly, PTEN specifically interacts with Rad52 and positively regulates its sumoylation. Taken together, these observations strongly suggest that PTEN may mediate DNA damage repair through interacting with and regulating Rad52 in the nucleus.
Citation Format: Byeong Hyeok Choi, Wei Dai. PTEN localizes to the nucleus and interacts with Rad52 in response to DNA damage. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2389. doi:10.1158/1538-7445.AM2014-2389
Abstract 2391: USP7 deubiquitinates XPC in response to ultraviolet light irradiation
Authors: He Jinshan , Zhu Qianzheng , Sharma Nidhi , Wani Gulzar , Han Chunhua , Qian Jiang , Pentz Kyle , Wang Qi-en , Wani Altaf A 
Published: May 2015

Abstract
Ultraviolet light (UV)-induced Xeroderma pigmentosum complementation group C (XPC) protein ubiquitination is mediated by an E3 ubiquitin ligase complex containing UV damaged-DNA binding protein. Here, we report that ubiquitin specific protease 7 (USP7) deubiquitinates XPC during NER. We have demonstrated that transiently compromising cellular USP7, by siRNA or specific inhibitor HBX41108, leads to accumulation of ubiquitinated forms of XPC. However, complete USP7 disruption causes an ubiquitin-mediated XPC degradation upon cellular irradiation. We show that USP7 interacts with XPC in vitro and in vivo. Overexpression of wild-type USP7, but not its catalytically inactive or interaction-defective mutants, reduces ubiquitinated forms of XPC. Importantly, USP7 efficiently deubiquitinates XPC-ubiquitin conjugates in deubiquitination assays in vitro. We further showed that valosin-containing protein (VCP)/p97 is required for UV-induced XPC degradation in USP7-deficient cells. VCP/p97 is readily recruited to DNA damage sites and co-localizes with XPC. Inhibition of VCP/p97 causes an accumulation of ubiquitinated XPC on DNA damaged chromatin. Moreover, USP7 disruption severely impairs the repair of cyclobutane pyrimidine dimers (CPD) and, to a lesser extent, affects the repair of 6-4 photoproducts (6-4PP). Taken together, our findings have uncovered an important role of USP7 in regulating NER via deubiquitinating XPC and by preventing its VCP/p97-regulated proteolysis (This work was supported by grants from NIH).
Citation Format: Jinshan He, Qianzheng Zhu, Nidhi Sharma, Gulzar Wani, Chunhua Han, Jiang Qian, Kyle Pentz, Qi-en Wang, Altaf A Wani. USP7 deubiquitinates XPC in response to ultraviolet light irradiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2391. doi:10.1158/1538-7445.AM2014-2391
Abstract 2393: The BARD1 BRCT domains are essential for maintenance of telomere integrity
Authors: Irminger-Finger Irmgard , Pilyugin Maxim , Ratajska Magdalena 
Published: May 2015

Abstract
BARD1 has tumor suppressor functions by binding to BRCA1 and to p53 via RING finger and ankyrin repeats, respectively. The BARD1-BRCA1 dimer has E3 ligase activity, and BARD1-p53 interaction induces apoptosis. The C-terminus of BARD1 is binding to many proteins that are targets of the BRCA1-BARD1 ubiquitin ligase, and expression of N-terminally truncated RING-less BARD1 isoforms was correlated with poor prognosis in various cancers, consistent with their oncogenic functions by antagonistic binding to target proteins.
Expression and interaction assays showed that the BARD1 BRCT domains were critically involved in telomere maintenance and interacted with the telomere binding protein TRF2. Overexpression of BARD1 or BRCA1 lead to TRF2 degradation, suggesting that TRF2 presents a novel target of the BARD1-BRCA1 E3 ubiquitination ligase. Repression of BARD1 or BRCA1 by siRNA leads to genetic instability, as shown before, and telomere alterations.
We observed distinct telomeric alterations in blood cells of patients with a BARD1 germline mutation that causes a translation stop and translation of a truncated protein lacking the BRCT domains. Cells of carriers of a BRCA1 mutation that disrupts the BARD1-BRCA1 interaction show similar telomere alterations. These in vitro and in vivo observations suggest that BARD1 and BRCA1 play distinct roles in maintaining telomere integrity in a dosage dependent manner.
BARD1δ, an isoform lacking RING and ankyrin motifs, but retaining the BRCT domains, is abundantly expressed in all cancers investigated so far. Overexpression of BARD1δ in vitro blocked cell cycle progression and induced chromosomal and telomere abnormalities, suggesting that BARD1δ also affected telomere integrity.
We conclude that the correct dose of BARD1 and/ or its BRCT domains is critically important for maintaining telomere integrity. Expression of BARD1δ in cancer, or reduced expression of BARD1 in mutation carriers causes chromosomal instability and promotes carcinogenesis and tumor progression.
Citation Format: Irmgard Irminger-Finger, Maxim Pilyugin, Magdalena Ratajska. The BARD1 BRCT domains are essential for maintenance of telomere integrity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2393. doi:10.1158/1538-7445.AM2014-2393
Abstract 2394: The role of DNA repair in breast cancer risk and recurrence
Authors: Matta Jaime L. , Suarez Erick , Vargas Wanda , Ortiz Carmen , Bayona Manuel , Morales Luisa 
Published: May 2015

Abstract
BACKGROUND: Breast cancer (BC) is a complex disease that is caused by multiple factors. Deficits in DNA repair capacity (DRC) are known to cause certain familial BC, and dysregulation of DRC develops with progressive carcinogenesis. However, the effect of DRC on carcinogenesis of sporadic breast tumors has not been well characterized_and the factors associated with DRC variability are still poorly understood. DNA repair is integral to maintain genomic integrity, and carcinogenesis occurs when efficient, effective DNA repair is impaired. Our laboratory has just finished the recruitment of nearly 1,200 women in a seven-year molecular epidemiology study focused on the role of DRC as a risk factor for BC. OBJECTIVE: Our aim is to present key findings on the role of DRC as a risk factor for BC and its potential association with BC recurrence. METHODS: A personal interview was conducted for soliciting information on BC risk factors. Among the 493 BC cases and 683 controls the DRC was measured in lymphocytes using a host cell reactivation assay with a luciferase reporter gene. We stratified the women with BC using the median of the DRC level and selected 70 women with a low DRC level (&lt;2.8%) who had been enrolled in the study for at least 5 years in order to assess the BC recurrence. RESULTS: Our 7 year study of DRC of female cohorts in Puerto Rico has shown that women with BC have a
DRC that, on average, is 51% lower than women without BC (P &lt; 0.001, Mann Whitney U-test). Women with low DRC have 6.8 (95%CI 5.2, 9.0) times the odds for BC when compared with women with high DRC level. So far, the overall BC recurrence was 17% and the 5-year mortality was 10%. Recurrence was primarily in the lung, liver, bone, or occurred as generalized metastatic disease. CONCLUSIONS: Using a large sample size (n=1,183 participants), we show that women with BC had on an average a 51% lower DRC than controls (P&lt;0.001). We also present the first data on the potential between a low DRC and risk of BC recurrence. With a larger sample size, we will test the hypothesis that low DRC can predict risk of BC recurrence. Supported by grants from the NCI Center to Reduce Health Disparities through the NIH-MBRS Program grants S06 GM008239-20, 9SC1CA182846-04 to PSMHS through JM and MBRS-RISE GM082406 through CO.
Citation Format: Jaime L. Matta, Erick Suarez, Wanda Vargas, Carmen Ortiz, Manuel Bayona, Luisa Morales. The role of DNA repair in breast cancer risk and recurrence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2394. doi:10.1158/1538-7445.AM2014-2394
Abstract 2395: Progression of structural change in breast cancer metastasis
Authors: Hartmaier Ryan J. , Lee Adrian V. 
Published: May 2015

Abstract
Structural variations (SVs) have been shown to be a major source of genetic instability in cancer and metastasis but remains understudied. This is due to: (1) the limited power of paired-end sequencing (PES) in detecting SVs that frequently occur around repetitive regions and (2) the large amount (4ug) of high-molecular weight DNA required for mate-pair sequencing (MPS), which is specifically designed to detect SVs even in repetitive regions. Importantly, DNA obtained from FFPE tissue is heavily sheared and therefore not suitable for MPS - excluding most metastatic tissues in tumor banks.
To overcome the barriers of MPS, we leveraged the University of Pittsburgh Rapid Autopsy Program and the Health Sciences Tissue Bank to obtain matched primary/metastatic frozen tumor samples from 6 patients (19 total tumor samples).
Multiple large-insert (3-5, 5-8, & 8-12 kb) mate-pair sequencing, was performed for each sample to obtain a complete catalogue of SVs. Additionally, whole exome sequencing was performed to identify point mutations and to de-convolute clonal evolution within each patient.
After removing SVs found in matched germline DNA, we identified extensive somatic SVs within the primary tumor that tended to decrease in metastatic samples. This is likely due to extensive genetic heterogeneity in the primary tumor that underwent clonal selection due to metastasis and/or treatment. Well-known hotspots (such as 17q), showed extensive intra- and inter- chromosomal SVs in both primary and metastatic tumors indicating that these are likely early and essential events in tumorgenesis. However, metastatic specific events also clustered with 17q suggesting that this region continues to play a role during metastasis. Somatic single-nucleotide variations (SNVs) revealed obvious high density clustering of mutations (kataegis) that overlapped with SV breakpoints. Further analysis revealed that these SNV clusters were primarily TT-TC, which is a signature of the deaminase APOBEC3B recently been shown to bind around dsDNA breaks and cause high levels of mutations. We have observed examples of kataegis as early, shared events and metastatic specific events indicating that kataegis is an ongoing process through metastasis.
Together these data show that extensive SV occurs during breast cancer tumorigenesis and metastasis and these SVs often co-occur with kataegis. As more samples and distant metastases are sequenced, RNA-seq will be used to help prioritize specific metastatic specific SVs for functional studies demonstrating the role in the development of the metastatic phenotype.
Citation Format: Ryan J. Hartmaier, Adrian V. Lee. Progression of structural change in breast cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2395. doi:10.1158/1538-7445.AM2014-2395
Abstract 2398: Activity of the PARP inhibitor olaparib in ATM-deficient gastric cancer: from preclinical models to the clinic
Authors: Hodgson Darren , Mason Helen , Oplustilova Lenka , Harbron Chris , Yin Xiaolu , Im Seock-Ah , Jones Helen , Zhongwu Lai , Dougherty Brian , McLoughlin Matthew , Bradford James , Dickinson Andrew , Fielding Anitra , Robertson Jane , Kim Woo-Ho , Womack Chris , Gu Yi , Bang Yung-Jue , Lau Alan , Barrett J. Carl , O'Connor Mark J. 
Published: May 2015

Abstract
Olaparib is an oral inhibitor of the Poly-(ADP-ribose)-polymerases (PARP-1, -2 and -3), and has demonstrated clinical activity in trials of patients with BRCA-deficient tumors. The BRCA1 and BRCA2 proteins are both important for the repair of DNA double strand breaks (DSBs) by homologous recombination repair (HRR) and sensitivity to olaparib has further been shown preclinically to extend to other DNA DSB repair factor deficiencies, including those in the ataxia telangiectasia mutated (ATM) protein.
We have demonstrated that a high proportion of gastric cancer (GC) cell lines (∼50%) are responsive (IC50 &lt;500 nM) to single agent olaparib and that characterization of their DNA repair status reveals that, as in breast and ovarian cancer, HRR deficiencies (HRD) can account at least in part for this. However, unlike breast and ovarian cancer cell lines, there is no strong correlation with platinum sensitivity, suggesting alternative drivers of response in the GC panel to HRD. Here, we demonstrate that low levels of ATM protein expression correlate with sensitivity of GC cell lines to olaparib, and moreover can be observed in approximately 15-20% of clinical gastric cancer samples when evaluated using ATM immunohistochemistry (IHC).
Based on these data, a Phase II GC trial has been carried out that enriches for patients with tumors having low or undetectable ATM IHC scores (H-score equivalent less than or equal to 10). Data from this clinical trial confirm activity (overall survival [OS] benefit HR=0.56, 95% CI: 0.35-0.87; P=0.010) in the overall population, which includes ATM tumor positive patients, and importantly, a substantially better OS benefit in the ATM-negative population (HR=0.35, 95% CI: 0.17-0.71; P=0.003). Together, these data provide an important example of a PARP inhibitor demonstrating both preclinical and clinical activity in a well defined but non-BRCA DNA repair deficient background.
Citation Format: Darren Hodgson, Helen Mason, Lenka Oplustilova, Chris Harbron, Xiaolu Yin, Seock-Ah Im, Helen Jones, Lai Zhongwu, Brian Dougherty, Matthew McLoughlin, James Bradford, Andrew Dickinson, Anitra Fielding, Jane Robertson, Woo-Ho Kim, Chris Womack, Yi Gu, Yung-Jue Bang, Alan Lau, J. Carl Barrett, Mark J. O'Connor. Activity of the PARP inhibitor olaparib in ATM-deficient gastric cancer: from preclinical models to the clinic. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2398. doi:10.1158/1538-7445.AM2014-2398
Abstract 24: HFE genotype affects tumor progression and macrophage behavior in a mouse model
Authors: Weston Cody L. , Alkhateeb Ahmed , Hund William , Connor James R. 
Published: May 2015

Abstract
Introduction: Studies suggest that iron metabolism is associated with tumor progression, but a mechanism and the relative importance of different iron handling proteins still remain to be elucidated. We investigated the effects of the frequently polymorphic high iron gene (HFE), on tumor growth. This study is significant because of the ability of HFE mutant protein to alter iron handling and because our previous studies have shown the presence of this mutation is associated with altered cancer phenotype in cells.
Hypothesis: Mutations in the HFE protein modify tumor progression and metastatic potential.
Methods: C57BL/6 mice possessing either H67D/H67D (H63D in humans) or WT/WT HFE genotype, aged 18 months, were injected subcutaneously with 4x106 B16F10 cells. After 2 weeks, mice were sacrificed and the tumors were weighed and prepared for analysis of RNA, protein, and histology. At the same time, plasma was collected by cardiac puncture. Animal methods were approved by our IACUC, protocol 04-166. RT-PCR analysis of tumors was performed using the Mouse Cancer Pathwayfinder Array (SABiosciences). In parallel, bone marrow derived macrophages were cultured to determine how B16F10 cell cultures react to conditioned media from macrophages of each genotype. ELISAs were performed for ferroportin and ferritin. Secreted cytokine and chemokine content of macrophage media was assessed with an ELISA array (Qiagen).
Results: H67D mice had significantly smaller tumors (t-test, P = 0.0166) after two weeks. The two-week time frame was selected because rapid tumor growth affected animal survival at longer incubations. Exploratory qRT-PCR analysis of tumors revealed that the H67D host may promote epithelial phenotype and suppress angiogenesis and growth. In culture, macrophages derived from H67D mice express higher levels of MCP1 (p = 0.0169). Conditioned media from the H67D macrophages was associated with significantly less B16F10 cell growth compared to WT (p &lt; 0.0001 MTT, p = 0.0008 BrdU). In macrophage cell lysates, H67D is associated with higher levels of Ferroportin (p = 0.0297), and WT macrophages showed higher iron levels in response to FAC (p = 0.0295).
Conclusions: Tumors grown in H67D mice are significantly lower in weight than control mice. Macrophages from H67D mice neither load iron nor support tumor cell proliferation as well as WT controls. Our data reveal the importance of HFE genotype on macrophage function and tumor growth. The H63D HFE allele is seen in approximately 15% of the human population so its impact on cancer studies is likely significant.
Citation Format: Cody L. Weston, Ahmed Alkhateeb, William Hund, James R. Connor. HFE genotype affects tumor progression and macrophage behavior in a mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 24. doi:10.1158/1538-7445.AM2014-24
Abstract 240: Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC-bZip transcription factors in estrogen-induced breast carcinogenesis
Authors: Chatterjee Anwesha , Ronghe Amruta , Abdalla Fatma , Bhat Hari K. 
Published: May 2015

Abstract
Epidemiological data and studies in rodent models strongly support the role of estrogens in the development of breast cancers. Exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature evidence and our studies strongly support the role of estrogen metabolism mediated oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated that antioxidants vitamin C (VC) or butylated hydroxyanisole (BHA) severely inhibit 17β-estradiol (E2)-induced breast tumor development in female ACI rats. The objective of this study was to characterize the role of CNC b-zip transcription factors in antioxidant-mediated prevention of breast cancer.
Human non-neoplastic breast epithelial cell line MCF-10A was treated with E2, VC, VC + E2, Resveratrol (Res) and Res + E2 for up to 72 hrs. mRNA and protein expression levels of phase-II detoxifying enzymes SOD1, SOD2, SOD3, GPx, NQO1 and transcription factors from CNC b-zip family: Nrf1, Nrf2 and Nrf3 were quantified after treatment with E2 and compared with that of cells treated with antioxidants either alone or in combination with E2.
The mRNA as well as protein expression levels of SOD3 and NQO1 were suppressed in MCF-10A cells treated with E2. There was no change in mRNA and protein expression levels of SOD1, SOD2 and GPX in MCF-10A cells treated with E2. Nrf2 mRNA and protein expression levels were also significantly suppressed in E2-treated MCF-10A cells. Vitamin C or Res treatment prevented E2-mediated decrease in SOD3, NQO1 and Nrf2 mRNA and protein expression levels. A significant increase in Nrf1 mRNA and protein expression levels in MCF-10A cells treated with E2 was noted. Further, treatment with antioxidants Res or VC also increased mRNA and protein expression levels of Nrf1. Nrf3 mRNA and protein expression levels were significantly increased in MCF-10A cells treated with E2. This induction was overcome by co-treatment with E2 and VC or Res.
Our studies demonstrate that antioxidant-mediated protection against estrogen-induced breast cancer could be through up regulation of phase-II detoxifying enzymes via an Nrf-dependent pathway involving a complex interplay among Nrfs 1, 2 and 3.
Note: This abstract was not presented at the meeting.
Citation Format: Anwesha Chatterjee, Amruta Ronghe, Fatma Abdalla, Hari K. Bhat. Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC-bZip transcription factors in estrogen-induced breast carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2014-240