bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 773: Inhibition of ubiquitin receptor ADRM1 for the treatment of metastatic breast cancer
Authors: Andrews Christopher , Yates Clayton , Karanam Balasubramanyam 
Published: June 2022

Abstract
Adhesion-regulating molecule 1 (ADRM1) is a polyubiquitin receptor on the 26S proteasome. ADRM1 is upregulated in many cancers. In this study, we evaluated the potential prognostic and predictive value of ADRM1 in breast cancer patients. We determined the expression of ADRM1 and its relationship to breast cancer subtypes, using the Cancer Genome Atlas dataset that contained racial and clinical outcomes data totaling 1108 patients. The ADRM1 mRNA expression levels were divided into quartiles to designate the ADRM1 high versus low expression designation. Karanam et. al developed an orally available proteasome inhibitor bis-benzylidine piperidone (RA190), that binds to the ubiquitin receptor RPN13/ADRM1 on the 19S regulatory particle of the proteasome and directly kills cancer cells by triggering proteotoxic stress. RA190 binds to cysteine 88 of ADRM1/RPN13, triggering rapid accumulation of high-molecular-weight poly-ubiquitinated proteins resulting in apoptosis. Up284 is one of a second generation of small molecules that mimic RA190 activity. The objective of this study is to verify the role of ubiquitin receptor RPN13/ADRM1 in metastatic breast cancer samples of European American and African American patients and identify the safe combination of regimens of bortezomib in combination with Up289 to mitigate recurrence, metastasis and reduce mortality in AA TNBC/QNBC. Clinically, this will reveal a new, hitherto unknown targeted regimen for AA QNBC. From the biological perspective, it will provide insights into the underlying molecular changes that are associated with health disparities. Currently available treatments are unable to eradicate metastatic breast cancer specifically those classified as QNBC. Our preliminary analysis of Cancer Genome Atlas (TCGA) indicated that ADRM1 expression is highly expressed in AA versus EA breast cancer patients, resulting in a worse overall survival. Further analysis of ADRM1 in QNBC patients indicated that it was significantly elevated predominantly in African American patients with QNBC.
Citation Format: Christopher Andrews, Clayton Yates, Balasubramanyam Karanam. Inhibition of ubiquitin receptor ADRM1 for the treatment of metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 773.
Abstract 782: Multiomic single cell sequencing identified regulatory elements in prostate cells
Authors: Tian Yijun , Soupir Alex , Wang Liang 
Published: June 2022

Abstract
Introduction: Despite significant progress, the genetic role of regulatory elements in gene expression is still poorly understood in prostate cells. Recent development in single cell sequencing by combining ATAC-seq and RNA-seq has made it possible to determine genome-wide linkages between chromatin accessibilities and gene expression.
Methods: To test the feasibility of using single cell multiome sequencing in dissecting regulatory linkages between chromatin accessibilities and gene expressions, we applied 10X Genomics Chromium Single Cell Multiome ATAC + Gene Expression platform to simultaneously encapsulate Tn5 transposase tagged nuclei from two prostate cell lines. We applied down-sampling linkage analysis to determine highly reproducible genome-wide associations between ATAC-seq peaks and RNA-seq gene expressions. To investigate the chromatin accessibilities related to human transcription factor binding sites, we scanned the JASPAR motif collection with genome-wide Tn5 insertion analysis.
Results: This study encapsulated 3,096 multiome RWPE-1 nuclei cultured in serum-free condition, 6,978 and 8,487 multiome LNCaP nuclei treated with methanol (LNCaP-M) or dihydrotestosterone (DHT, LNCaP-D). Our analysis captured 210,990, 264,802, and 278,154 ATAC-seq peaks from RWPE-1, LNCaP-M, and LNCaP-D by macs2 narrow peak model (FDR q&lt;0.01), which included over 90% peaks identified by bulk ATAC-seq datasets. Through downsampling linkage analysis, we identified 1,595, 2,507, and 4,183 linkage associations between ATAC-seq and RNA-seq from the above three experiments, respectively. Scatter plots showed that the correlation coefficient of the linkage association was negatively associated with the distance between ATAC-seq and RNA-seq signals. By comparing to bulk ChIP-seq data from RWPE-1 cells, we confirmed that the single cell ATAC-seq peaks in linkages were co-localized at histone modified regions, including H3K4me1 (25.7%), H3K27ac (14.3%), and H3K4me3 (4.9%). JASPAR database (634 motifs) search found that the Tn5 footprints surrounding AR, NR3C1, and NR3C2 motifs in LNCaP-D showed significantly higher enrichment than that of the LNCaP-M group, indicating increased androgen receptor DNA binding following DHT treatment. Interestingly, in RWPE-1 cells harboring TP53 p.P72R polymorphism (rs1042522), we found differential Tn5 footprints surrounding TP53 binding motif between its ATAC-seq subclusters at whole genome scale.
Conclusion: Our preliminary data in prostate cell lines outlined a regulatory landscape of single-cell resolution. Multiomic single cell sequencing will help locate regulatory elements and target genes.
Citation Format: Yijun Tian, Alex Soupir, Liang Wang. Multiomic single cell sequencing identified regulatory elements in prostate cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 782.
Abstract 797: Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation
Authors: Udden S. M. Nashir , Alluri Prasanna G. 
Published: June 2022

Abstract
Acquired mutations in ESR1 gene that encodes for Estrogen Receptor (ER) are a common mechanism of acquired resistance to endocrine therapies in breast cancer. However, the role of such mutations in modulation of cell’s response to radiation therapy is poorly understood. In this study, we define the role of ESR1 mutations in altering response to radiation therapy in pre-clinical models of ER-positive breast cancer. To investigate whether ESR1 mutations influence cell’s response to radiation therapy, we employed ER-positive MCF7 and T47D cell lines which have been genome edited to knock-in two of the most common ESR1 mutations, such as Y537S and D538G, found in breast cancer patients. Clonogenic survival assays were carried out to characterize differences in radiation sensitivity of these cells. g-H2AX and Comet assays were employed to study the differences in residual unrepaired DNA damage following radiation in these cell lines. MCF7 cell line-derived xenografts harboring the wild type or mutant ESR1 were employed to study differences in radiation resistance of these tumors in vivo. We found that ER-positive cell lines harboring ESR1 mutations exhibited profound resistance to radiation therapy compared to cell lines harboring the wild type ESR1. These radioresistant cell lines also demonstrated significantly less unrepaired DNA damage following radiation therapy. We observed that mice harboring ESR1 mutant xenografts showed remarkable resistance to radiation therapy. We also observed that ESR1 mutations, which confer resistance to endocrine therapies, also confer profound resistance to radiation therapy. Our findings suggest that oligometastatic ER-positive breast cancer patients who are being treated with radiation therapy (such as those enrolled in NRG BR002 trial) may show significant differences in response to radiation therapy based on their ESR1 mutation status. Recent studies are also exploring the use of neo-adjuvant endocrine therapy in non-metastatic ER-positive breast cancer patients. It is conceivable that some of these patients may acquire ESR1 mutations under selective pressure of neoadjuvant endocrine therapy and may respond poorly to subsequent adjuvant radiation therapy. Overall, our findings support potential personalization of radiation treatments in breast cancer patients based on ESR1 mutation status, heralding an era of precision radiation oncology.
Citation Format: S. M. Nashir Udden, Prasanna G. Alluri. Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 797.
Abstract 804: Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97
Authors: Krastev Dragomir B. , Lord Chris 
Published: June 2022

Abstract
Poly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumor activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, “trapped” PARP1. Here we have elucidated a pathway that process trapped PARP1. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with either a rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME)-based approach or PARP1 Apex2-proximity labelling linked to mass-spectrometry, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. These experiments demonstrated an increase in the SUMO1/2 modifications upon trapping, as well as an interaction with the ubiquitin-regulated p97 ATPase (aka VCP). Subsequent experiments demonstrated that upon trapping, PARP1 is SUMOylated by the SUMO-ligase PIAS4 and subsequently ubiquitinated by the SUMO-targeted E3-ubiquitin ligase, RNF4, events that promote p97 recruitment and p97 ATPase-mediated removal of trapped-PARP1 from chromatin. Consistently, small molecule p97 complex inhibitors, including a metabolite of the clinically-used drug disulfiram, CuET that acts as a p97 sequestration agent, prolong PARP1 trapping and thus enhance PARPi-induced cytotoxicity in homologous recombination defective tumor cells and patient-derived tumor organoids. Taken together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 from chromatin and the response of homologous recombination defective tumor cells to PARPi.
Citation Format: Dragomir B. Krastev, Chris Lord. Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 804.
Abstract 819: ERBB4 mediates IL10-induced growth of EGFR-independent colon tumors
Authors: McGill Michael P. , Rojas Carolina Mantilla , Threadgill David W. 
Published: June 2022

Abstract
ERBB4 is commonly over-expressed in human CRC, however the utility of ERBB4 as a target for colorectal cancer (CRC) therapeutics is largely unexplored. Our group recently identified a molecular subtype of CRC that arises independent of EGFR and displays a more aggressive growth phenotype than those dependent on EGFR. The robust growth phenotype of EGFR-independent tumors can be in part attributed to upregulation of IL10 signaling. In addition, EGFR-independent tumors display a significant upregulation of Erbb2 and Erbb4 transcripts in both spontaneous and sporadic CRC mouse models, perhaps compensating for the loss of EGFR. To investigate the importance of other ERBB receptors in EGFR-independent CRC tumor progression, we ablated Erbb4 to interrogate its influence on tumor development in vivo using a conditional allele of Erbb4tm1Fej (Erbb4f). ERBB4-deficient ApcMin/+ mice (ApcMin/+, ErbB4f/f, Tg(Vil1-Cre)) were established and used to show that ERBB4 ablation in the intestinal epithelia results in a significant decrease in the number of intestinal and colon tumors. Polyps lacking ERBB4 were also significantly reduced size, contrary to what is observed with loss of EGFR. We also recently developed ERBB2-deficient ApcMin/+ mice, and preliminary results suggest that Erbb2 ablation also results in a decrease in intestinal and colon tumor number and size. Consistent with data from EGFR-independent tumors, transcriptomic analysis of ERBB4-deficient intestinal tumors predicted down-regulation of IL10 signaling, which was validated through Il10 and Socs3 qPCR. To complement our findings, the observed down-regulation of Il10 and Socs3 at the transcript level corresponded with a significant decrease in IL10 levels in the serum of mice harboring ERBB4 deficient tumors when compared to mice without tumors. Furthermore, we found that transcript levels of Erbb4 significantly decreased after anti-IL10 treatment of EGFR-independent tumors in vivo. This illustrates a possible negative feedback loop whereby neutralizing IL10 also leads to a reduction of Erbb4 expression, further reducing IL10 signaling. Taken together, the data suggest that the absence of EGFR triggers Erbb4 upregulation, implicating an important role for ERBB4 in EGFR-independent colon tumor growth. These results suggest that therapeutic targeting of ERBB4 may lead to a reduction in IL10 signaling and reduced intestinal polyp multiplicity and size in EGFR-independent tumors and inform the development of novel approaches to treat CRC that exhibit aberrant expression of EGFR and ERBB4.
Citation Format: Michael P. McGill, Carolina Mantilla Rojas, David W. Threadgill. ERBB4 mediates IL10-induced growth of EGFR-independent colon tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 819.
Abstract 820: Nuclear receptor TLX inhibits cancer cell intrinsic properties required for triple-negative breast cancer progression
Authors: Nelczyk Adam T. , Gamage Hashni E. Vidana , Ma Liqian , McHenry Michael T. , Henn Madeline A. , Kadiri Mohammed , Wang Yu , Gupta Anasuya Das , Krawczynska Natalia , He Sisi , Spinella Michael J. , Nelson Erik R. 
Published: June 2022

Abstract
The primary purpose of our work was to characterize the effects of the nuclear receptor TLX (NR2E1) in triple-negative breast cancer (TNBC) in order to evaluate its potential therapeutic value in a subtype of breast cancer that has proven particularly challenging to treat, primarily due to the lack of targeted modes of intervention. Unfortunately, breast cancer continues to be the second deadliest form of cancer among women in the United States. Considering the substantial public health implications, development of new therapeutic strategies for highly aggressive breast cancer subtypes, such as TNBC, is imperative. While the function of nuclear receptors such as the estrogen and androgen receptors has been extensively characterized in cancers of the breast and prostate respectively, due in part to their amenable nature to ligand modulation, it is likely that other nuclear receptors may represent therapeutic targets for these malignancies. Indeed, probing of available clinical datasets demonstrated that nuclear receptor TLX is most highly expressed in basal and estrogen receptor (ER)-negative breast cancer patients, and that ER-negative patients with higher TLX expression had increased relapse-free and overall survival. Therefore, we hypothesized that TLX could influence the pathophysiology of TNBC. Utilizing a stable overexpression model in the TNBC cell lines, MDA-MB-231 and MDA-MB-468, we have shown that TLX can inhibit critical oncogenic properties in the in vitro setting, including proliferation, migration and invasion. Furthermore, xenograft and lung colonization studies demonstrated that TLX continued to exert anti-oncogenic effects in the in vivo environment. In agreement with these results, transcriptomic analysis of TLX-overexpressing cells and xenograft tumors showed that TLX can regulate genes and pathways that are known to play crucial roles in the growth and metastatic dissemination of cancer. As previously published works have identified several putative TLX ligands, our findings demonstrating that TLX functions as an anti-cancer factor in TNBC provides a strong rationale for future research aimed at therapeutically targeting this nuclear receptor.
Citation Format: Adam T. Nelczyk, Hashni E. Vidana Gamage, Liqian Ma, Michael T. McHenry, Madeline A. Henn, Mohammed Kadiri, Yu Wang, Anasuya Das Gupta, Natalia Krawczynska, Sisi He, Michael J. Spinella, Erik R. Nelson. Nuclear receptor TLX inhibits cancer cell intrinsic properties required for triple-negative breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 820.
Abstract 829: p53 dimers elicit tumor suppressive activities through an altered metabolic program
Authors: Gencel-Augusto Jovanka , Su Xiaoping , Lozano Guillermina 
Published: June 2022

Abstract
p53 is the most frequently mutated gene in human cancer. As a tetrameric transcription factor, mutation of the p53 Tetramerization Domain (TD) is a mechanism by which cancers abrogate wild-type (WT) p53 function. p53 TD mutations result in a protein that preferentially forms monomers or dimers. Although it is accepted that tetrameric p53 is required for full tumor suppressive activities, the physiological relevance of monomeric and dimeric states of p53 is not well understood. We have established the first in vivo models for hot-spot p53 TD mutants, p53R339P and p53A344D (murine), that result in monomeric and dimeric p53, respectively. These models closely resemble Li-Fraumeni Syndrome (LFS) patients with germline p53 TD alterations and will be used to characterize their physiological activities.
p53R339P and p53A344D proteins failed to form tetramers. These mutants were deficient in their transactivation ability for canonical p53 target genes, and unable to induce apoptosis following IR. Both p53 TD mutant mice rescued the p53-dependent embryo lethality caused by genetic deletion of Mdm2, suggesting these are loss-of-function alleles. Monomeric p53 bearing mice succumbed mainly to thymic lymphomas (~60%), with a median survival similar to p53-/- mice (~130 days). Dimeric p53 bearing mice displayed lower incidence of thymic lymphomas (~25%) and longer survival (~180 days). Analyses of the transcriptomes elicited after DNA damage in normal thymus revealed that the p53 signaling pathway is dampened in dimeric p53 thymi. However, under basal conditions, p53 dimers upregulate a lipid metabolic program that is associated with PPAR activation. Further RNA sequencing of common metabolic tissues of the mouse (pancreas, liver, and intestine) revealed that they upregulate lipid-related metabolic programs in p53 dimer samples. This study describes, for the first time, the consequences of altering p53 tetramerization in vivo. Monomer and dimer forms of p53 do not retain most WT p53 features. p53 dimers may exert tumor suppression as seen by extended survival and tumor spectra shift. p53 dimer-specific activities on PPAR signaling and lipid metabolism may explain these phenotypes. These activities are possible therapeutic targets for LFS patients.
Citation Format: Jovanka Gencel-Augusto, Xiaoping Su, Guillermina Lozano. p53 dimers elicit tumor suppressive activities through an altered metabolic program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 829.
Abstract 842: ADAR and DDX54 promote genomic stability in breast cancer cells
Authors: Ryu Sua , Cottrell Kyle A. , Soto-Torres Luisángely , Schabb Angela , Weber Jason D. 
Published: June 2022

Abstract
Adenosine deaminase acting on RNA (ADAR) is an RNA-editing enzyme that binds dsRNA and converts adenosine to inosine. ADAR promotes cell survival and proliferation in multiple types of tumors, including breast cancer. However, the mechanism of ADAR-driven oncogenicity is not fully established. We focused on ADAR p110, the constitutively expressed and nuclear-localized isoform, and its role in managing genotoxic stress in cancer. ADAR p110 is involved in resolving R-loops, the DNA-RNA hybrids produced during transcription, and DNA damage response (DDR). We sought to elucidate the mechanism of ADAR-associated R-loop resolution and DDR that can be targeted in breast cancer. To identify ADAR-interacting proteins, proximity labeling was performed using ADAR p110 fused to ascorbate peroxidase (APEX2), followed by mass spectrometry. Among the positively enriched hits, known ADAR-interacting proteins associated with R-loop and DDR were validated by immunoprecipitation and immunofluorescence. DEAD-box helicase DDX54 was among the nine RNA helicases interacting with ADAR. DDX54 and ADAR showed an additive effect on preventing γH2AX signal. Additionally, knockdown (KD) of DDX54 increased ADAR expression, whereas ADAR KD did not affect DDX54 expression. These results suggest that DDX54 coordinates with ADAR to prevent genotoxic stress in breast cancer cells. As DDX54 and ADAR are both associated with R-loop resolution and DDR, we hypothesize that DDX54 and ADAR suppress R-loop accumulation and/or other types of genotoxic stress. This may be through independent pathways despite the physical interaction between ADAR and DDX54.
Citation Format: Sua Ryu, Kyle A. Cottrell, Luisángely Soto-Torres, Angela Schabb, Jason D. Weber. ADAR and DDX54 promote genomic stability in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 842.
Abstract 843: Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73gamma in tumorigenesis and obesity via leptin
Authors: Kong Xiangmudong , Sun Wenqiang , Zhang Jin , Chen xinbin 
Published: June 2022

Abstract
TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α-η). Interestingly, TAp73 is shown to have opposing functions in tumorigenesis but the mechanism remains unclear. Here, we showed that deletion of exon 11 (E11) switches p73α to p73γ, the latter of which has oncogenic activities. Moreover, E11-deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, chronic inflammation and tumor incidence, indicating that p73γ cannot compensate p73α for tumor suppression and fertility. E11-deficient mice were also prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Mechanistically, we showed that Leptin, a pleiotropic adipocytokine, was highly induced by p73γ and necessary for p73γ-mediated oncogenic activity. Importantly, p73α-γ isoform switch was detected in dog lymphomas and human prostate carcinomas along with elevated expression of Leptin. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism.
Citation Format: Xiangmudong Kong, Wenqiang Sun, Jin Zhang, xinbin Chen. Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73gamma in tumorigenesis and obesity via leptin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 843.