tbuckley/cabot-search huggingface dataset:
Abstract 4864: Role of AIB1 Δ -4 in malignant progression of breast cancer
Authors: Ghada M. Sharif, Virginie Ory, Anton Wellstein, Anna Riegel
Journal: Cancer Research (2017)

Abstract The nuclear co activator AIB1 is amplified and/or overexpressed in up to 60 % of breast cancers. We have previously described a splice variant of AIB1 (Δ4) missing exon 4 that results in an N-terminally truncated protein. Full length AIB1 transcriptional function can be repressed by the tumor supressor ANCO1/ANKRD11. However, Δ4 is missing the ANCO1 binding domain and is not transcriptionally suppressed. More metastatic variants of isogenic breast or colon cancer cell lines have significantly increased levels of Δ4 relative to full length protein. Δ4 levels also increase in breast tissue samples as they transition in malignant progression. We conjectured that small increases in Δ4 protein in the cell could have potent effects on malignant progression. To determine the functional significance of Δ4 in malignant progression we developed DCIS (ductal carcinoma in situ) cell lines that only express this isoform and not the full length protein. We engineered these lines by using CRISPR technology targeted at the exon 3/4 splice junction. The resulting lines were significantly more invasive in ECIS endothelial invasion assays. In vivo, intracardiac zebrafish injections of the Δ4-DCIS lines showed higher extravasation from the tail vasculature compared to the parental line. Subcutaneous xenografts in athymic nude mice grew larger tumors, presented more invasive lesions and metastases. Also, Δ4-DCIS spheres growing in matrigel, showed disorganization and enhanced invasion into the matrix. In conclusion these data suggest a model where the increased splicing of AIB1 to the Δ4 variant alters transcription at specific target genes and contributes to the metastatic phenotype. Citation Format: Ghada M. Sharif, Virginie Ory, Anton Wellstein, Anna Riegel. Role of AIB1 Δ -4 in malignant progression of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4864. doi:10.1158/1538-7445.AM2017-4864
Genome-wide Association Study of Susceptibility to Particulate Matter–Associated QT Prolongation
Authors: Rahul Gondalia, Christy L. Avery, Melanie D. Napier, Raúl Méndez-Giráldez, James D. Stewart, Colleen M. Sitlani, Yun Li, Kirk C. Wilhelmsen, Qing Duan, Jeffrey Roach, Kari E. North, Alexander P. Reiner, Zhu-Ming Zhang, Lesley F. Tinker, Jeff D. Yanosky, Duanping Liao, Eric A. Whitsel
Journal: Environmental Health Perspectives (2017)

Background: Ambient particulate matter (PM) air pollution exposure has been associated with increases in QT interval duration (QT). However, innate susceptibility to PM-associated QT prolongation has not been characterized. Objective: To characterize genetic susceptibility to PM-associated QT prolongation in a multi-racial/ethnic, genome-wide association study (GWAS). Methods: Using repeated electrocardiograms (1986–2004), longitudinal data on PM&lt;10μm in diameter (PM10), and generalized estimating equations methods adapted for low-prevalence exposure, we estimated approximately 2.5×106 SNP×PM10 interactions among nine Women’s Health Initiative clinical trials and Atherosclerosis Risk in Communities Study subpopulations (n=22,158), then combined subpopulation-specific results in a fixed-effects, inverse variance-weighted meta-analysis. Results: A common variant (rs1619661; coded allele: T) significantly modified the QT-PM10 association (p=2.11×10−8). At PM10 concentrations &gt;90th percentile, QT increased 7 ms across the CC and TT genotypes: 397 (95% confidence interval: 396, 399) to 404 (403, 404) ms. However, QT changed minimally across rs1619661 genotypes at lower PM10 concentrations. The rs1619661 variant is on chromosome 10, 132 kilobase (kb) downstream from CXCL12, which encodes a chemokine, stromal cell-derived factor 1, that is expressed in cardiomyocytes and decreases calcium influx across the L-type Ca2+ channel. Conclusions: The findings suggest that biologically plausible genetic factors may alter susceptibility to PM10-associated QT prolongation in populations protected by the U.S. Environmental Protection Agency’s National Ambient Air Quality Standards. Independent replication and functional characterization are necessary to validate our findings. https://doi.org/10.1289/EHP347
Abstract 1271: Genetic variants in the 16q24.3 region of melanocortin-1-receptor (<i>MC1R)</i> and prostate cancer risk: A Mendelian randomization analysis of 39,000 cases and 25,000 controls
Authors: Stephanie J. Weinstein, Tracy M. Layne, Jiaqi Huang, Eric Karlins, Stephen J. Chanock, Demetrius Albanes, the PRACTICAL Consortium
Journal: Cancer Research (2017)

Abstract We previously reported that men with naturally red hair had a significantly lower risk of prostate cancer (HR=0.46, 95% CI 0.24-0.89) compared with the most prevalent hair color, light brown (Br J Cancer 2013;109(3):747-750). The red hair phenotype is encoded by variants in the melanocortin-1-receptor (MC1R) gene that controls expression of the eumelanin and pheomelanin pigments. In order to re-examine this association through the relatively unbiased Mendelian randomization approach, we examined single nucleotide polymorphisms (SNPs) in and near MC1R in relation to prostate cancer risk using data from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. The analysis includes 38,868 men diagnosed with prostate cancer and 25,210 controls from 35 studies participating in PRACTICAL Consortium (Nat Gen 2014;46(10)1103-1109). Logistic regression modeling was used to estimate the odds ratio (OR) and confidence interval (CI) for the per allele prostate risk associations with 148 genotyped SNPs and 164 imputed SNPs. Variants demonstrating nominal significance (alpha-error p&amp;lt;0.05) as well as those reaching a stringent Bonferroni threshold of p&amp;lt;0.0003 adjustment for multiple comparisons were examined. We identified prostate cancer risk associations with 30 genotyped and 36 imputed polymorphisms that were nominally significant, three of which achieved Bonferroni significance and were in a region of 16q24.3 that includes MC1R, GAS8 (growth arrest specific-8, an alleged tumor suppressor that is deleted in some prostate cancers), and transcription factor-25 (TCF25). These were rs4628973 and rs3743824 that were in high LD (r2=0.931; prostate cancer risk associations p=0.00029 and 0.00023, respectively), as well as rs6500461 that was independently associated with risk (r2=0.20 with rs4628973; p=0.00020). This large-scale Mendelian randomization analysis suggests genetic variants near MC1R, which directs melanocyte melanin synthesis, secretion and human pigmentation, may be associated with risk of prostate cancer. Citation Format: Stephanie J. Weinstein, Tracy M. Layne, Jiaqi Huang, Eric Karlins, Stephen J. Chanock, Demetrius Albanes, the PRACTICAL Consortium. Genetic variants in the 16q24.3 region of melanocortin-1-receptor (MC1R) and prostate cancer risk: A Mendelian randomization analysis of 39,000 cases and 25,000 controls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1271. doi:10.1158/1538-7445.AM2017-1271
Abstract 4317: EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes
Authors: Yongguang Tao, Shuang Liu, Yiqun Jiang
Journal: Cancer Research (2017)

Abstract Ferroptosis has emerged as a new form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms of ferroptosis remain poorly defined. We demonstrate that Lymphoid-specific helicase (LSH), a DNA methylation modifier, interacts with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2. These effects are dependent on iron and lipid reactive oxygen species. We further show that EGLN1 and c-Myc directly activate LSH expression by inhibiting HIF-1α. Finally, we demonstrate that LSH functions as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis for a c-Myc/EGLN1-mediated induction of LSH expression to inhibit ferroptosis, which can be exploited for the development of therapeutic agents to target ferroptosis in cancer. Note: This abstract was not presented at the meeting. Citation Format: Yongguang Tao, Shuang Liu, Yiqun Jiang. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2017-4317
Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells
Authors: Im-Sook Song, Niramol Savaraj, Zahid H. Siddik, Peiman Liu, Yingjie Wei, Chun Jing Wu, Macus Tien Kuo
Journal: Cancer Research (2004)

Recent studies have shown that the mammalian highaffinity copper transporter encoded by Ctr1 is involved in the uptake of cisplatin. However, the roles of hCtr1 in cisplatin-sensitive and cisplatin-resistant mammalian cells have not been investigated. Here, we show that, of five cisplatin-resistant cell lines, only one (SR2) exhibited substantial reduction in hCtr1 expression as compared with that in its sensitive line small cell lung cancers (SCLC), whereas copper efflux transporters ATP7A and ATP7B were not significantly altered. SR2 exhibited crossresistance to carboplatin but not to oxaliplatin. Transfection of expression hemagglutinin-tagged hCtr1 cDNA into SCLC and SR2 cells enhanced the uptake of copper, cisplatin, carboplatin, and oxaliplatin, suggesting that hCtr1 transporter can transport these platinum-based drugs. Whereas increased sensitivities to all these platinum drugs were observed in hCtr1-transfected SCLC cells, increased sensitivities to cisplatin and carboplatin but not to oxaliplatin were observed in hCtr1-transfected SR2 cells. These results suggest that SR2 acquired an additional unique intracellular resistance mechanism to oxaliplatin. Finally, using hCtr1 deletion mutants, we showed that the NH2-terminal domain of hCtr1 was involved in transporting all these platinum-based antitumor agents. These results collectively show the importance of hCtr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant variants. [Mol Cancer Ther 2004;3(12):1543–9]
Abstract 1541: The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation
Authors: Jeffim N. Kuznetsov, Tristan Aguero, Stefan Kurtenbach, Matthew G. Field, Mary Lou King, J William Harbour
Journal: Cancer Research (2017)

Abstract Introduction: Our lab discovered that mutations in the tumor suppressor BAP1 are strongly associated with metastasis and death in patients with uveal melanoma. Subsequently, other cancers have been found to harbor BAP1 mutations, including skin melanoma, kidney cancer, mesothelioma and others. Germline BAP1 mutations are responsible for a newly described genetic cancer syndrome. Therapeutic molecules that reverse the effects of BAP1 mutations could represent a potent new treatment strategy for BAP1-mutant cancers. Unfortunately, there are several obstacles to developing such therapies. First, BAP1 is a tumor suppressor that is inactivated by mutations, such that targeted therapy would need to be directed against downstream effectors that are deregulated by BAP1 loss. Second, the effectors of BAP1 that are relevant to cancer are not known. Interestingly, most known proteins that interact with Bap1 are developmental epigenetic regulators such as Asxl1/2, Cbx1/3 and Kdm1b. Third, BAP1 is difficult to study in cultured cells because BAP1 loss results in cell cycle exit and stem cell-like behavior. These obstacles led us to shift to Xenopus laevis as an in vivo developmental model to study the functions of BAP1. Results and conclusions: Loss of BAP1 during embryo development results in a failure to turn off pluripotency genes such as ventx 1, ventx2 (Xenopus orthologues of the mammal gene nanog), oct 25, oct 91 (Xenopus orthologues of the mammal gene oct3/4) and pax3, and a failure to induce lineage specification genes such as the prospective epidermis marker keratin1 and the melanocyte precursor marker sox10. This block in the shift from pluripotency to differentiation programs results in a delay in gastrulation, neural crest specification and migration, mesodermal differentiation and other phenotypes. The BAP1-deficient phenotype can be rescued by Xenopus or human wildtype BAP1 or by the histone deacetylase inhibitor SAHA (vorinostat). We conclude that BAP1 is a fundamental regulator of multiple developmental lineages, including the neural crest from which melanomas arises, and that this in vivo model can be used to screen for novel therapeutic compounds that reverse the phenotypic effects of BAP1 loss. Citation Format: Jeffim N. Kuznetsov, Tristan Aguero, Stefan Kurtenbach, Matthew G. Field, Mary Lou King, J William Harbour. The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1541. doi:10.1158/1538-7445.AM2017-1541
Abstract 479: Modeling miRNA induced silencing in breast cancer with PARADIGM
Authors: Andrew J. Sedgewick, Panayiotis V. Benos, Shahrooz Rabizadeh, Patrick Soon-Shiong, Charles J. Vaske
Journal: Cancer Research (2017)

Abstract Introduction: MicroRNAs play an important role in regulation of gene expression and are known biomarkers for breast cancer as well as other malignancies. PARADIGM is a pathway based algorithm that allows for integration of multiple genomic data types with a curated pathway database to make pathway activity predictions. We added a model of gene silencing due to miRNA to the PARADIGM algorithm in order to study miRNA expression in a pathway context. Results: We curated a set of 7751 miRNA-mRNA interactions from the intersection of 3 target prediction algorithms. These interactions involved 66 miRNA and 2814 mRNA transcripts. We ran this model on global DNA copy number, RNAseq and miRNAseq data from 697 patients in the TCGA breast cancer cohort, and studied changes in the interactions between miRNAs and their targets between different tumor subtypes. The median activity of the RNA-induced silencing complex (RISC) predicted by our model is significantly higher in Basal tumors than other subtypes. In addition, RISC activity is significantly associated with overall survival of patients with Luminal A tumors. The miRNA-target pairs with the largest correlation changes between Basal and Luminal A subtypes were enriched for putative oncogenes and oncomirs. The mRNA targets are involved in a number of important signaling pathways including PI3K-AKT, JAK-STAT, and Ras. Many of these highly differential links involved the miR-16 family of miRNAs which are known tumor suppressors. miR-16 shows significantly lower activity in basal tumors than other subtypes. Conclusions: By looking at changes in miRNA-target links between tumor subtypes, our algorithm was able to identify both miRNAs and target genes involved in pathways relevant to breast cancer. Our predictions of overall RNA-induced silencing activity show prognostic value in both determining subtype and predicting overall survival within subtypes. Citation Format: Andrew J. Sedgewick, Panayiotis V. Benos, Shahrooz Rabizadeh, Patrick Soon-Shiong, Charles J. Vaske. Modeling miRNA induced silencing in breast cancer with PARADIGM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 479. doi:10.1158/1538-7445.AM2017-479
Abstract LB-320: Reconstituting B55/protein phosphatase 2A activity in B55/PP2A-defective prostate cancer cells suppresses proliferation and tumorigenicity through pleiotropic mechanisms
Authors: Ziran Zhao, Alison Kurimchak, Petr Makhov, Katherine Johnson, Vladimir Kolenko, James Duncan, Xavier Graña
Journal: Cancer Research (2017)

Abstract Prostate cancer accounts for close to 30,000 deaths annually in the United States. The most frequent alteration in the prostate oncogenome landscape is loss of chromosome 8p, which is also observed in other epithelial tumors. This region harbors NKX3.1, a prostate specific tumor suppressor, but 8p copy number loss does not correlate with its mRNA expression. The PPP2R2A gene, which encodes a regulatory subunit of protein phosphatase 2 (PP2A) designated B55, is located in 8p21.2 and is hemizygously lost in more that 50% of prostate adenocarcinomas. TCGA data analysis shows that hemizygous loss of PPP2R2A correlates with its reduced expression, poorer prognosis and that loss of PPP2R2A increases with metastasis to more than 80%. Of note, while homozygous loss is less common (4-10%), deletion of other subunits of the B55, but not other PP2A regulatory families, increases dramatically with metastasis despite their independent chromosomal locations. However, functional evidence that PPP2R2A acts as an haploinsufficient tumor suppressor and the potential mechanisms implicated are lacking. We have identified prostate cancer (PrCa) cell lines with reduced expression of B55 and shown that reconstitution of B55 expression reduces proliferation and induces senescence and loss of viability. B55 reconstitution in PC3 cells, an AR-negative model of human castration-resistant prostate cancer (CRPC), also blocks transformation in vitro and tumorigenicity in SCID mice. Reconstitution of B55 in PCa cells with reduced expression (PC3 and DU145 cells) induces cell cycle defects in G1, G2/M and mitosis diminishing and delaying phosphorylation of pRB pocket proteins and mitotic substrates and altering associated kinase networks. Mitogenic signaling is also attenuated. Importantly, the effects of B55 reconstitution are at least partially mimicked via treatment of these cells with PP2A activating drugs, which have anti-tumorigenic activity, indicating that development of specific B55/PP2A activating drugs targeting the unaltered B55 alleles remaining in PCa cells may have therapeutic potential for a high proportion of prostate tumors and perhaps other epithelial tumors such as luminal B breast and ovarian cancers which share this alteration. Citation Format: Ziran Zhao, Alison Kurimchak, Petr Makhov, Katherine Johnson, Vladimir Kolenko, James Duncan, Xavier Graña. Reconstituting B55/protein phosphatase 2A activity in B55/PP2A-defective prostate cancer cells suppresses proliferation and tumorigenicity through pleiotropic mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-320. doi:10.1158/1538-7445.AM2017-LB-320
Abstract 5942: Collagen proly-hydroxylase regulates breast cancer progression and chemoresistance
Authors: Gaofeng Xiong, Ren Xu
Journal: Cancer Research (2017)

Abstract Collagen prolyl hydroxylation (P4H), an enzyme hydroxylating proline residues in -X-Pro-Gly- sequences, is a potential therapeutic target for the disorders associated with increased collagen deposition. Upregulation of collagen prolyl-4-hydroxylase in cancer cells is required for breast cancer promotion. P4HA1 mRNA levels were significantly upregulated in triple-negative breast cancer (TNBC) compared to other cancer subtypes. Increased mRNA levels of P4HA1 correlated with poor clinical outcome in breast cancer patients. Silencing P4HA1 expression or treatment with the P4HA inhibitor significantly inhibited cell proliferation and suppressed aggressive phenotypes of breast cancer cells in 3D culture, accompanied by reduced deposition of collagen. We found that activation of the P4HA1 in TNBC cells enhanced cancer cell stemness. We also found that knockdown of P4HA1 inhibited mammary tumor growth and metastasis to lungs in xenograft models. Inhibition of P4HA1 activity with the P4H inhibitor sensitized TNBC to the docetaxel treatment in the patient-derived organoid (PDO) and xenograft models. Therefore, these results suggest the crucial role of P4HA1 in breast cancer progression and that targeting collagen P4H is a promising strategy to inhibit tumor progression and to sensitize TNBC to chemotherapy. Citation Format: Gaofeng Xiong, Ren Xu. Collagen proly-hydroxylase regulates breast cancer progression and chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5942. doi:10.1158/1538-7445.AM2017-5942