bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table S2 from A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution
Authors: Walsh Kyle M. , de Smith Adam J. , Hansen Helen M. , Smirnov Ivan V. , Gonseth Semira , Endicott Alyson A. , Xiao Jianqiao , Rice Terri , Fu Cecilia H. , McCoy Lucie S. , Lachance Daniel H. , Eckel-Passow Jeanette E. , Wiencke John K. , Jenkins Robert B. , Wrensch Margaret R. , Ma Xiaomei , Metayer Catherine , Wiemels Joseph L.
Published: March 2023

Top SNP associations in the 9p21.3 region evaluated in Hispanic ALL patients from CCLS and validated in European-ancestry ALL patients from COG, with functional annotation.
Supplementary Figure S4 from Germinal Centers Determine the Prognostic Relevance of Tertiary Lymphoid Structures and Are Impaired by Corticosteroids in Lung Squamous Cell Carcinoma
Authors: Siliņa Karīna , Soltermann Alex , Attar Farkhondeh Movahedian , Casanova Ruben , Uckeley Zina M. , Thut Helen , Wandres Muriel , Isajevs Sergejs , Cheng Phil , Curioni-Fontecedro Alessandra , Foukas Periklis , Levesque Mitchell P. , Moch Holger , Linē Aija , van den Broek Maries
Published: March 2023

The analysis of the correlation between gene expression and histological parameters or survival.
Supplementary Figure Legends from Distinct Subtypes of Gastric Cancer Defined by Molecular Characterization Include Novel Mutational Signatures with Prognostic Capability
Authors: Li Xiangchun , Wu William K.K. , Xing Rui , Wong Sunny H. , Liu Yuexin , Fang Xiaodong , Zhang Yanlin , Wang Mengyao , Wang Jiaqian , Li Lin , Zhou Yong , Tang Senwei , Peng Shaoliang , Qiu Kunlong , Chen Longyun , Chen Kexin , Yang Huanming , Zhang Wei , Chan Matthew T.V. , Lu Youyong , Sung Joseph J.Y. , Yu Jun
Published: March 2023

Supplementary Figure Legends
Supplementary Figure Legends from Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide
Authors: Kuo Wei-Ting , Lee Tsung-Chun , Yu Linda Chia-Hui
Published: March 2023

Legends for supplementary figures and videos.
Supplementary Dataset 2 from Distinct Subtypes of Gastric Cancer Defined by Molecular Characterization Include Novel Mutational Signatures with Prognostic Capability
Authors: Li Xiangchun , Wu William K.K. , Xing Rui , Wong Sunny H. , Liu Yuexin , Fang Xiaodong , Zhang Yanlin , Wang Mengyao , Wang Jiaqian , Li Lin , Zhou Yong , Tang Senwei , Peng Shaoliang , Qiu Kunlong , Chen Longyun , Chen Kexin , Yang Huanming , Zhang Wei , Chan Matthew T.V. , Lu Youyong , Sung Joseph J.Y. , Yu Jun
Published: March 2023

DNA repair gene mutations, SMGs, and hotspot mutations in RGC and HGC.
Supplementary Figure 2 from Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide
Authors: Kuo Wei-Ting , Lee Tsung-Chun , Yu Linda Chia-Hui
Published: March 2023

Knockdown efficiency of LPS receptor subunits and PKCζ in primary mouse colonic tumor spheroids and human adenocarcinoma cell lines.
Supplementary Figure and Table Legends from Antitumor Properties of an IgG2-Enhanced Next-Generation MET Monoclonal Antibody That Degrades Wild-Type and Mutant MET Receptors
Authors: Yang Yan , Mandiyan Sreekala , Robinson Brett S. , McMahon Gerald
Published: March 2023

Legends for Supplementary Figures S1-S4 and Supplementary Table S1.
Supplemental Figures 1 through 8 from mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer
Authors: Driscoll David R. , Karim Saadia A , Sano Makoto , Gay David M. , Jacob Wright , Yu Jun , Mizukami Yusuke , Gopinathan Aarthi , Jodrell Duncan I. , Evans T.R. Jeffry , Bardeesy Nabeel , Hall Michael N. , Quattrochi Brian J. , Klimstra David S. , Barry Simon T. , Sansom Owen J. , Lewis Brian C. , Morton Jennifer P.
Published: March 2023

Figure S1: Loss of Rictor does not prevent pancreatic formation or function. Figure S2: Rictor deletion decreases proliferation in PanIN1 lesions. Figure S3: Rictor deletion alters CDKI and BMI1 expression and localization. Figure S4: Rictor deletion does not affect response to caerulein-induced pancreatic injury. Figure S5: Absence of mTORC2 activity increases the nuclear expression of CDKIs in PanIN1 lesions driven by KrasG12D and caerulein-induced pancreas injury. Figure S6: Rictor knockdown impairs the transformed phenotype in murine PDAC cells. Figure S7: AZD2014 treatment blocks signaling downstream of mTORC1 and mTORC2. Figure S8: AZD2014 and AZD8186 co-treatment blocks downstream mTORC2 targets.
Supplementary movie S3 from Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization
Authors: Konotop Gleb , Bausch Elena , Nagai Tomoaki , Turchinovich Andrey , Becker Natalia , Benner Axel , Boutros Michael , Mizuno Kensaku , Krämer Alwin , Raab Marc Steffen
Published: March 2023

Representative fluorescence time-lapse microscopy comparing mitotic events of H2B-mCherry-ÃŽÂ±-tubulin-EGFP- HeLa cells treated with 2 Ã,ÂµM CP-673451.
Supplementary movie S1 from Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization
Authors: Konotop Gleb , Bausch Elena , Nagai Tomoaki , Turchinovich Andrey , Becker Natalia , Benner Axel , Boutros Michael , Mizuno Kensaku , Krämer Alwin , Raab Marc Steffen
Published: March 2023

Representative fluorescence time-lapse microscopy comparing mitotic events of H2B-mCherry-ÃŽÂ±-tubulin-EGFP- HeLa cells treated with DMSO.
Supplementary data from Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization
Authors: Konotop Gleb , Bausch Elena , Nagai Tomoaki , Turchinovich Andrey , Becker Natalia , Benner Axel , Boutros Michael , Mizuno Kensaku , Krämer Alwin , Raab Marc Steffen
Published: March 2023

Extended experimental procedures Supplementary Fig. S1. Effect of CP-673451 and Crenolanib on centrosome amplification in U2OS cells. Supplementary Fig. S2. Crenolanib prolongs of mitotic duration. Supplementary Fig. S3. CP-673451 activates cofilin in a dose-dependent manner in a variety of cancer cell lines. Supplementary Fig. S4. Inhibition of cofilin phosphorylation by LIMKi3 and Damnacanthal. Supplementary Fig. S5. Immunoblot analysis showing transient overexpression of different cofilin constructs and representative images of transfection efficiencies in U2OS-EGFP-PLK4 cells. Supplementary Fig. S6. Validation of SSH knock-down by real-time PCR. Supplementary Fig. S7. Effect of CP-673451 on SSH1 phosphatase activity. Supplementary Fig. S8. Immunoblot analysis of different cell lines showing that CP-673451 increases Akt and MEK1/2 phosphorylation under normal cultivation conditions. Supplementary Table S2. Average percentages of multipolar telophases in various cell lines after 24 hours of exposure to CP-673451 or crenolanib.
Supplementary Figure S3 from Kv1.3 Channels Mark Functionally Competent CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Cancer
Authors: Chimote Ameet A. , Hajdu Peter , Sfyris Alexandros M. , Gleich Brittany N. , Wise-Draper Trisha , Casper Keith A. , Conforti Laura
Published: March 2023

Assessment of background staining for non-conjugated antibodies.
SI Figure 5 from TLR Adaptor Protein MYD88 Mediates Sensitivity to HDAC Inhibitors via a Cytokine-Dependent Mechanism
Authors: New Maria , Sheikh Semira , Bekheet Mina , Olzscha Heidi , Thezenas Marie-Laetitia , Care Matthew A. , Fotheringham Susan , Tooze Reuben M. , Kessler Benedikt , La Thangue Nicholas B.
Published: March 2023

High-resolution heat map of top gene signatures and GO terms enriched for top MYD88 correlated genes in ABC DLBCL
Supplementary Table S5 from Molecular Evolution Patterns in Metastatic Lymph Nodes Reflect the Differential Treatment Response of Advanced Primary Lung Cancer
Authors: Um Sang-Won , Joung Je-Gun , Lee Hyun , Kim Hojoong , Kim Kyu-Tae , Park Jinha , Hayes D. Neil , Park Woong-Yang
Published: March 2023

Table S5. Mapping statistics of sequencing reads of RNA sequencing
Supplemental Table S5 from CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma
Authors: Yoshimoto Toyoki , Tanaka Miwa , Homme Mizuki , Yamazaki Yukari , Takazawa Yutaka , Antonescu Cristina R. , Nakamura Takuro
Published: March 2023

Unregulated genes in CDS vs ES
Supplementary Figure 6 from T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia
Authors: Jing Weiqing , Gershan Jill A. , Holzhauer Sandra , Weber James , Palen Katie , McOlash Laura , Pulakanti Kirthi , Wesley Erin , Rao Sridhar , Johnson Bryon D. , Riese Matthew J.
Published: March 2023

Assessment of activation markers on APC after ACT
Supplementary Figures S1-8 from An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer
Authors: Kenkel Justin A. , Tseng William W. , Davidson Matthew G. , Tolentino Lorna L. , Choi Okmi , Bhattacharya Nupur , Seeley E. Scott , Winer Daniel A. , Reticker-Flynn Nathan E. , Engleman Edgar G.
Published: March 2023

Supplementary Figures S1-8. Fig. S1: CD11b+CD11c+MHC-II+ cells exhibit DC phenotype and accumulate at multiple metastatic sites. Fig. S2: PDAC cells produce large amounts of GM-CSF and stimulate Mo-DC differentiation. Fig. S3: Liver DC from tumor-bearing mice efficiently activate T cells in conventional assays. Fig. S4: Metastasis-associated DC stimulate nTreg proliferation while suppressing CD8 T cells through PD-1 ligand expression. Fig. S5: MGL2+ cells exhibit DC phenotype and their depletion activates multiple lymphocyte populations. Fig. S6: Blocking PD-L2 reduces metastasis without affecting primary tumor burden. Fig. S7: PD-L2+ and MGL+ cells are present in human PDAC tissues. Fig. S8: Development and function of CD11b+ DC in PDAC metastasis.
Data from Cancer Cell Lines as Genetic Models of Their Parent Histology: Analyses Based on Array Comparative Genomic Hybridization
Authors: Greshock Joel , Nathanson Katherine , Martin Anne-Marie , Zhang Lin , Coukos George , Weber Barbara L. , Zaks Tal Z.
Published: March 2023

Abstract
Tumor-derived cell lines are used as in vitro cancer models, but their ability to accurately reflect the phenotype and genotype of the parental histology remains questionable, given the prevalence of documented cell line–specific cytogenetic changes. We have addressed the issue of whether copy number alterations seen in tumor-derived cell lines reflect those observed in studies of fresh tissue by carrying out a meta-analysis of array-based comparative genomic hybridization data that considers both copy number alteration frequencies and the occurrence of cancer gene amplifications and homozygous deletions. Pairwise correlation comparisons between the data sets of seven diagnosis-specific matched tumor and cell line groups indicate that the trends in aberration frequencies are highly correlated between tumors and cell line sets of matched cancer histology relative to unmatched pairings. Despite their similarities, cell lines showed uniformly higher locus-specific alteration frequencies (P = 0.004) and several recurring cell line–specific alterations emerged. These include the previously documented losses of 13q and 9p and gains of 20q, as well as additional undescribed cell line–specific gains of 5p, 7p, and 17q and losses of 18q and 4q. These results indicate that, on average, cell lines preserve in vitro the genetic aberrations that are unique to the parent histology from which they were derived while acquiring additional locus-specific alterations. These data may enable a more predictive understanding of individual cell lines as in vitro models of cancer biology and therapy. [Cancer Res 2007;67(8):3594–600]
Data from Degradation of Lung Adenoma Susceptibility 1, a Major Candidate Mouse Lung Tumor Modifier, Is Required for Cell Cycle Progression
Authors: Liu Yan , Vikis Haris G. , Yi Yijun , Futamura Manabu , Wang Yian , You Ming
Published: March 2023

Abstract
We have previously identified murine lung adenoma susceptibility 1 (Las1) as the pulmonary adenoma susceptibility 1 candidate gene. Las1 has two natural alleles, Las1-A/J and Las1-B6. Las1 encodes an 85-kDa protein with uncharacterized biological function. In the present study, we report that Las1 is an unstable protein and the rapid destruction of Las1 depends on the ubiquitin-proteasome pathway. Las1 is a new microtubule-binding protein and Las1 associated with tubulin is not ubiquitinated. We further show that Las1-A/J is a more stable protein than Las1-B6. Las1 is expressed in the G2 phase of the cell cycle and that ubiquitin-proteasome–mediated Las1 destruction occurs in mitosis. Overexpression of Las1-A/J inhibits normal E10 cell proliferation and induces a defective cytokinesis. The differential degradation of Las1-A/J and Las-B6 has important implications for its intracellular function and may eventually explain Las1-A/J in lung tumorigenesis. [Cancer Res 2007;67(21):10207–13]
Data from Transcription Factor Stat5 Synergizes with Androgen Receptor in Prostate Cancer Cells
Authors: Tan Shyh-Han , Dagvadorj Ayush , Shen Feng , Gu Lei , Liao Zhiyong , Abdulghani Junaid , Zhang Ying , Gelmann Edward P. , Zellweger Tobias , Culig Zoran , Visakorpi Tapio , Bubendorf Lukas , Kirken Robert A. , Karras James , Nevalainen Marja T.
Published: March 2023

Abstract
The molecular mechanisms underlying progression of prostate cancer to the hormone-independent state are poorly understood. Signal transducer and activator of transcription 5a and 5b (Stat5a/b) is critical for the viability of human prostate cancer cells. We have previously shown that Stat5a/b is constitutively active in high-grade human prostate cancer, but not in normal prostate epithelium. Furthermore, activation of Stat5a/b in primary human prostate cancer predicted early disease recurrence. We show here that transcription factor Stat5a/b is active in 95% of clinical hormone-refractory human prostate cancers. We show for the first time that Stat5a/b synergizes with androgen receptor (AR) in prostate cancer cells. Specifically, active Stat5a/b increases transcriptional activity of AR, and AR, in turn, increases transcriptional activity of Stat5a/b. Liganded AR and active Stat5a/b physically interact in prostate cancer cells and, importantly, enhance nuclear localization of each other. The work presented here provides the first evidence of synergy between AR and the prolactin signaling protein Stat5a/b in human prostate cancer cells. [Cancer Res 2008;68(1):236–48]
Data from Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells
Authors: Jacinto Filipe V. , Ballestar Esteban , Ropero Santiago , Esteller Manel
Published: March 2023

Abstract
CpG island promoter hypermethylation of tumor suppressor genes is a common hallmark of human cancer, and new large-scale epigenomic technologies might be useful in our attempts to define the complete DNA hypermethylome of tumor cells. Here, we report a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKO cells). Using methylated DNA immunoprecipitation methodology in conjunction with promoter microarray analyses, we found that DKO cells experience a significant loss of hypermethylated CpG islands. Further characterization of these candidate sequences shows CpG island promoter hypermethylation and silencing of genes with potentially important roles in tumorigenesis, such as the Ras guanine nucleotide-releasing factor (RASGRF2), the apoptosis-associated basic helix-loop transcription factor (BHLHB9), and the homeobox gene (HOXD1). Hypermethylation of these genes occurs in premalignant lesions and accumulates during tumorigenesis. Thus, our results show the usefulness of DNMT genetic disruption strategies combined with methylated DNA immunoprecipitation in searching for unknown hypermethylated candidate genes in human cancer that might aid our understanding of the biology of the disease and be of potential translational use. [Cancer Res 2007;67(24):11481–6]
Data from Hoxb7 Inhibits Transgenic HER-2/neu–Induced Mouse Mammary Tumor Onset but Promotes Progression and Lung Metastasis
Authors: Chen Hexin , Lee Ji Shin , Liang Xiaohui , Zhang Huiping , Zhu Tao , Zhang Zhe , Taylor M. Evangeline , Zahnow Cynthia , Feigenbaum Lionel , Rein Alan , Sukumar Saraswati
Published: March 2023

Abstract
Our previous studies have shown that HOXB7 mRNA is overexpressed in ∼50% of invasive breast carcinomas and promotes tumor progression in breast cancer cells grown as xenografts in mice. In silico analysis of published microarray data showed that high levels of HOXB7 predict a poor outcome in HER-2–positive (P = 0.046), but not in HER-2–negative breast cancers (P = 0.94). To study the function of HOXB7 in vivo in the context of HER-2 overexpression, we generated mouse mammary tumor virus (MMTV)-Hoxb7 transgenic mice, and then crossed them with MMTV-HER-2/neu transgenic mice. In the mice carrying both Hoxb7 and HER-2/neu transgenes, Hoxb7 plays a dual role in mammary tumorigenesis. In double transgenic mice, overexpression of Hoxb7 delayed tumor onset and lowered tumor multiplicity. However, consistent with the clinical data, once the tumors appeared, their growth was faster and metastasis to the lungs occurred at a higher frequency. Our data show, for the first time, that deregulated expression of Hoxb7 in mammary tumor cells can significantly modulate HER-2/neu-oncogene induced tumorigenesis in vivo. [Cancer Res 2008;68(10):3637–44]
Data from Histone Deacetylase Inhibitors Induce Cell Death Selectively in Cells That Harbor Activated kRasV12: The Role of Signal Transducers and Activators of Transcription 1 and p21
Authors: Klampfer Lidija , Huang Jie , Shirasawa Senji , Sasazuki Takehiko , Augenlicht Leonard
Published: March 2023

Abstract
Histone deacetylase (HDAC) inhibitors (HDACi) show potent and selective antitumor activity despite the fact that they induce histone hyperacetylation in both normal and tumor cells. In this study, we showed that the inducible expression of kRasV12 in nontransformed intestinal epithelial cells significantly lowered the mitochondrial membrane potential (MMP) and sensitized cells to HDACi-induced apoptosis. Consistent with our finding that colon cancer cell lines with mutant Ras have reduced expression of signal transducers and activators of transcription 1 (STAT1), we showed that inducible expression of mutant Ras markedly decreased both basal and inducible expression of STAT1, a transcription factor with tumor suppressor activity. To investigate whether reduced expression of STAT1 in cells that harbor mutant Ras contributes to their increased sensitivity to HDACi, we silenced the expression of STAT1 in HKe-3 cells with small interfering RNA. Despite the fact that silencing of STAT1 was not sufficient to alter the MMP, STAT1 deficiency, like Ras mutations, sensitized cells to apoptosis induced by HDACi. We showed that the induction of p21 by HDACi was significantly impaired in HKe-3 cells with silenced STAT1 expression and showed that the ability of butyrate to activate p21 transcription was diminished in STAT1-deficient HKe-3 cells. Finally, we used cells with targeted deletion of p21 to confirm that p21 protects cells from butyrate-induced apoptosis, strongly suggesting that in these cells STAT1 deficiency promotes butyrate-induced apoptosis through impaired induction of p21. Our data therefore establish that Ras mutations, and consequent reduction in the expression of STAT1, underlie the increased susceptibility of transformed cells to undergo apoptosis in response to treatment with inhibitors of HDAC activity. [Cancer Res 2007;67(18):8477–85]
Data from Molecular Signature of MT1-MMP: Transactivation of the Downstream Universal Gene Network in Cancer
Authors: Rozanov Dmitri V. , Savinov Alexei Y. , Williams Roy , Liu Kang , Golubkov Vladislav S. , Krajewski Stan , Strongin Alex Y.
Published: March 2023

Abstract
Invasion-promoting MT1-MMP is directly linked to tumorigenesis and metastasis. Our studies led us to identify those genes, the expression of which is universally linked to MT1-MMP in multiple tumor types. Genome-wide expression profiling of MT1-MMP–overexpressing versus MT1-MMP–silenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P < 0.00001). These genes included regulators of energy metabolism (NNT), trafficking and membrane fusion (SLCO2A1 and ANXA7), signaling and transcription (NR3C1, JAG1, PI3Kδ, and CK2α), chromatin rearrangement (SMARCA1), cell division (STK38/NDR1), apoptosis (DAPK1), and mRNA splicing (SNRPB2). Our subsequent extensive analysis of cultured cells, tumor xenografts, and cancer patient biopsies supported our data mining. Our results suggest that transcriptional reprogramming of the specific downstream genes, which themselves are associated with tumorigenesis, represents a distinctive “molecular signature” of the proteolytically active MT1-MMP. We suggest that the transactivation activity of MT1-MMP contributes to the promigratory cell phenotype, which is induced by this tumorigenic proteinase. The activated downstream gene network then begins functioning in unison with MT1-MMP to rework the signaling, transport, cell division, energy metabolism, and other critical cell functions and to commit the cell to migration, invasion, and, consequently, tumorigenesis. [Cancer Res 2008;68(11):4086–96]
Data from ODC1 Is a Critical Determinant of MYCN Oncogenesis and a Therapeutic Target in Neuroblastoma
Authors: Hogarty Michael D. , Norris Murray D. , Davis Kimberly , Liu Xueyuan , Evageliou Nicholas F. , Hayes Candace S. , Pawel Bruce , Guo Rong , Zhao Huaqing , Sekyere Eric , Keating Joanna , Thomas Wayne , Cheng Ngan Ching , Murray Jayne , Smith Janice , Sutton Rosemary , Venn Nicola , London Wendy B. , Buxton Allen , Gilmour Susan K. , Marshall Glenn M. , Haber Michelle
Published: March 2023

Abstract
Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have coordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis. High-risk tumors without MYCN amplification also overexpress ODC1, the rate-limiting enzyme in polyamine biosynthesis, when compared with lower-risk tumors, suggesting that this pathway may be pivotal. Indeed, elevated ODC1 (independent of MYCN amplification) was associated with reduced survival in a large independent neuroblastoma cohort. As polyamines are essential for cell survival and linked to cancer progression, we studied polyamine antagonism to test for metabolic dependence on this pathway in neuroblastoma. The Odc inhibitor α-difluoromethylornithine (DFMO) inhibited neuroblast proliferation in vitro and suppressed oncogenesis in vivo. DFMO treatment of neuroblastoma-prone genetically engineered mice (TH-MYCN) extended tumor latency and survival in homozygous mice and prevented oncogenesis in hemizygous mice. In the latter, transient Odc ablation permanently prevented tumor onset consistent with a time-limited window for embryonal tumor initiation. Importantly, we show that DFMO augments antitumor efficacy of conventional cytotoxics in vivo. This work implicates polyamine biosynthesis as an arbiter of MYCN oncogenesis and shows initial efficacy for polyamine depletion strategies in neuroblastoma, a strategy that may have utility for this and other MYC-driven embryonal tumors. [Cancer Res 2008;68(23):9735–45]
Data from CAAT/Enhancer Binding Protein Homologous Protein–Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells
Authors: Lin Yi-Dan , Chen Shuzhen , Yue Ping , Zou Wei , Benbrook Doris M. , Liu Shengquan , Le Thanh C. , Berlin K. Darrell , Khuri Fadlo R. , Sun Shi-Yong
Published: March 2023

Abstract
The flexible heteroarotinoids (Flex-Het) represent a novel type of atypical retinoids lacking activity in binding to and transactivating retinoid receptors. Preclinical studies have shown that Flex-Hets induce apoptosis of cancer cells while sparing normal cells and exhibit anticancer activity in vivo with improved therapeutic ratios over conventional retinoid receptor agonists. Flex-Hets have been shown to induce apoptosis through activation of the intrinsic apoptotic pathway. The present study has revealed a novel mechanism underlying Flex-Het–induced apoptosis involving induction of death receptor 5 (DR5). The representative Flex-Het SHetA2 effectively inhibited the growth of human lung cancer cells in cell culture and in mice. SHetA2 induced apoptosis, which could be abrogated by silencing caspase-8 expression, indicating that ShetA2 triggers a caspase-8–dependent apoptosis. Accordingly, SHetA2 up-regulated DR5 expression, including cell surface levels of DR5, and augmented tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis. Importantly, small interfering RNA (siRNA)–mediated blockade of DR5 induction conferred cell resistance to SHetA2-induced apoptosis, as well as SHetA2/TRAIL-induced apoptosis. These results show that DR5 induction is a key component of apoptosis induced by SHetA2 or by SHetA2 combined with TRAIL. SHetA2 exerted CAAT/enhancer-binding protein homologous protein (CHOP)–dependent transactivation of the DR5 promoter. Consistently, SHetA2 induced CHOP expression, which paralleled DR5 up-regulation, whereas siRNA-mediated blockage of CHOP induction prevented DR5 up-regulation, indicating CHOP-dependent DR5 up-regulation by SHetA2. Collectively, we conclude that CHOP-dependent DR5 up-regulation is a key event mediating SHetA2-induced apoptosis. [Cancer Res 2008;68(13):5335–44]
Data from Pten Haploinsufficiency Accelerates Formation of High-Grade Astrocytomas
Authors: Kwon Chang-Hyuk , Zhao Dawen , Chen Jian , Alcantara Sheila , Li Yanjiao , Burns Dennis K. , Mason Ralph P. , Lee Eva Y.-H. P. , Wu Hong , Parada Luis F.
Published: March 2023

Abstract
We previously reported that central nervous system (CNS) inactivation of Nf1 and p53 tumor suppressor genes in mice results in the development of low-grade to high-grade progressive astrocytomas. When the tumors achieve high grade, they are frequently accompanied by Akt activation, reminiscent of the frequent association of PTEN mutations in human high-grade glioma. In the present study, we introduced CNS heterozygosity of Pten into the Nf1/p53 astrocytoma model. Resulting mice had accelerated morbidity, shortened survival, and full penetrance of high-grade astrocytomas. Haploinsufficiency of Pten accelerated formation of grade 3 astrocytomas, whereas loss of Pten heterozygosity and Akt activation coincided with progression into grade 4 tumors. These data suggest that successive loss of each Pten allele may contribute to de novo formation of high-grade astrocytoma and progression into glioblastoma, respectively, thus providing insight into the etiology of primary glioblastoma. The presence of ectopically migrating neural stem/progenitor lineage cells in presymptomatic Pten-deficient mutant brains supports the notion that these tumors may arise from stem/progenitor cells. [Cancer Res 2008;68(9):3286–94]
Data from Stromal Transforming Growth Factor-β Signaling Mediates Prostatic Response to Androgen Ablation by Paracrine Wnt Activity
Authors: Placencio Veronica R. , Sharif-Afshar Ali-Reza , Li Xiaohong , Huang Hongxia , Uwamariya Consolate , Neilson Eric G. , Shen Michael M. , Matusik Robert J. , Hayward Simon W. , Bhowmick Neil A.
Published: March 2023

Abstract
Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. Transient elevation of transforming growth factor-β (TGF-β) occurs after androgen ablation. To determine the role of TGF-β on prostate response to androgen ablation, conditional TGF-β type II receptor knockout mouse models of the epithelia (Tgfbr2NKX3.1KO) and stromal fibroblasts (Tgfbr2fspKO) were used. After castration, the prostates of Tgfbr2NKX3.1KO mice had apoptosis levels similar to those expected for control Tgfbr2floxE2/floxE2 mice. Prostates of Tgfbr2fspKO mice, however, had reduced regression and high levels of proliferation associated with canonical Wnt activity throughout the glandular epithelia regardless of androgen status. In contrast, Tgfbr2floxE2/floxE2 prostates had epithelial canonical Wnt activity only in the surviving proximal ducts after castration. In vitro studies showed that androgen antagonist, bicalutamide, transiently elevated both Tgfbr2floxE2/floxE2 and Tgfbr2fspKO stromal expression of Wnt-2, Wnt-3a, and Wnt-5a. The neutralization of Wnt signaling by the expression of secreted frizzled related protein-2 (SFRP-2) resulted in decreased LNCaP prostate epithelial cell proliferation in stromal conditioned media transfer experiments. In vivo tissue recombination studies using Tgfbr2fspKO prostatic stromal cells in combination with wild-type or SV40 large T antigen expressing epithelia resulted in prostates that were refractile to androgen ablation. The expression of SFRP-2 restored the Tgfbr2fspKO-associated prostate responsiveness to androgen ablation. These studies reveal a novel TGF-β, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts after androgen ablation while supporting proximal duct survival. [Cancer Res 2008;68(12):4709–18]
Data from Oncogene-Mediated Inhibition of Glycogen Synthase Kinase 3β Impairs Degradation of Prolactin Receptor
Authors: Plotnikov Alexander , Li Ying , Tran Thai H. , Tang Weigang , Palazzo Juan P. , Rui Hallgeir , Fuchs Serge Y.
Published: March 2023

Abstract
Prolactin receptors (PRLr) expressed in a majority of breast cancer are activated by prolactin and growth hormone. The PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser349, which, when phosphorylated, recruits the βTrcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that constitutive oncogenic signaling downstream of ErbB2 and Ras stabilizes PRLr via inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) on Ser9. Importantly, inactivation of GSK3β correlates with elevated levels of PRLr protein in clinical human breast cancer specimens. Additional studies using pharmacologic, biochemical, and genetic approaches reveal that GSK3β is a bona fide PRLr kinase that phosphorylates PRLr on Ser349 and is required for the recognition of PRLr by βTrcp, as well as for PRLr ubiquitination and degradation. [Cancer Res 2008;68(5):1354–61]
Data from Equilibrium between Host and Cancer Caused by Effector T Cells Killing Tumor Stroma
Authors: Zhang Bin , Zhang Yi , Bowerman Natalie A. , Schietinger Andrea , Fu Yang-Xin , Kranz David M. , Rowley Donald A. , Schreiber Hans
Published: March 2023

Abstract
The growth of solid tumors depends on tumor stroma. A single adoptive transfer of CD8+ CTLs that recognize tumor antigen–loaded stromal cells, but not the cancer cells because of MHC restriction, caused long-term inhibition of tumor growth. T cells persisted and continuously destroyed CD11b+ myeloid-derived, F4/80+ or Gr1+ stromal cells during homeostasis between host and cancer. Using high-affinity T-cell receptor tetramers, we found that both subpopulations of stromal cells captured tumor antigen from surrounding cancer cells. Epitopes on the captured antigen made these cells targets for antigen-specific T cells. These myeloid stromal cells are immunosuppressive, proangiogenic, and phagocytic. Elimination of these myeloid cells allowed T cells to remain active, prevented neovascularization, and prevented tumor resorption so that tumor size remained stationary. These findings show the effectiveness of adoptive CTL therapy directed against tumor stroma and open a new avenue for cancer treatments. [Cancer Res 2008;68(5):1563–71]
Data from Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel
Authors: Sawai Ayana , Chandarlapaty Sarat , Greulich Heidi , Gonen Mithat , Ye Qing , Arteaga Carlos L. , Sellers William , Rosen Neal , Solit David B.
Published: March 2023

Abstract
Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are found in a subset of patients with lung cancer and correlate with response to EGFR tyrosine kinase inhibitors (TKI). Resistance to these agents invariably develops, and current treatment strategies have limited efficacy in this setting. Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), induce the degradation of EGFR and other Hsp90 interacting proteins and may thus have utility in tumors dependent upon sensitive Hsp90 clients. We find that the EGFR mutations found most commonly in patients with lung adenocarcinoma who respond to EGFR TKIs are potently degraded by 17-AAG. Although the expression of wild-type EGFR was also down-regulated by 17-AAG, its degradation required higher concentrations of drug and a longer duration of drug exposure. In animal models, a single dose of 17-AAG was sufficient to induce degradation of mutant EGFR and inhibit downstream signaling. 17-AAG treatment, at its maximal tolerated dose, caused a significant delay in H3255 (L858R EGFR) xenograft growth but was less effective than the EGFR TKI gefitinib. 17-AAG alone delayed, but did not completely inhibit, the growth of H1650 and H1975 xenografts, two EGFR mutant models which show intermediate and high levels of gefitinib resistance. 17-AAG could be safely coadministered with paclitaxel, and the combination was significantly more effective than either drug alone. These data suggest that Hsp90 inhibition in combination with chemotherapy may represent an effective treatment strategy for patients whose tumors express EGFR kinase domain mutations, including those with de novo and acquired resistance to EGFR TKIs. [Cancer Res 2008;68(2):589–96]
Data from Wnt/β-Catenin Signaling Contributes to Activation of Normal and Tumorigenic Liver Progenitor Cells
Authors: Yang Wen , Yan He-Xin , Chen Lei , Liu Qiong , He Ya-Qin , Yu Le-Xing , Zhang Shu-Hui , Huang Dan-Dan , Tang Liang , Kong Xiao-Ni , Chen Chao , Liu Shu-Qin , Wu Meng-Chao , Wang Hong-Yang
Published: March 2023

Abstract
Adult hepatic progenitor (oval) cells are facultative stem cells in liver, which participate in a range of human liver diseases, including hepatocellular carcinoma (HCC). However, the molecular pathways regulating the expansion and differentiation of these cells are poorly understood. We show that active Wnt/β-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively active β-catenin mutant promotes expansion of the oval cell population in the regenerated liver. More importantly, we identify a subpopulation of less differentiated progenitor-like cells in HCC cell lines and primary HCC tissues, which are defined by expression of the hepatic progenitor marker OV6 and endowed with endogenously active Wnt/β-catenin signaling. These OV6+ HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy compared with OV6− tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation, whereas inhibition of β-catenin signaling leads to a decrease in the proportion of OV6+ cells. In addition, the chemoresistance of OV6+ HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targeting β-catenin. These results highlight the importance of the Wnt/β-catenin pathway in activation and expansion of oval cells in normal rodent models and human HCCs. OV6+ tumor cells may represent the cellular population that confers HCC chemoresistance, and therapies targeted to the Wnt/β-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy. [Cancer Res 2008;68(11):4287–95]
Data from Bin3 Deletion Causes Cataracts and Increased Susceptibility to Lymphoma during Aging
Authors: Ramalingam Arivudainambi , Duhadaway James B. , Sutanto-Ward Erika , Wang Yan , Dinchuk Joseph , Huang Minzhou , Donover Preston S. , Boulden Janette , McNally Lois M. , Soler Alejandro P. , Muller Alexander J. , Duncan Melinda K. , Prendergast George C.
Published: March 2023

Abstract
Bin3 encodes an evolutionarily conserved and ubiquitously expressed member of the BAR superfamily of curved membrane and GTPase-binding proteins, which includes the BAR, PCH/F-BAR, and I-BAR adapter proteins implicated in signal transduction and vesicular trafficking. In humans, Bin3 maps to chromosome 8p21.3, a region widely implicated in cancer suppression that is often deleted in non–Hodgkin's lymphomas and various epithelial tumors. Yeast studies have suggested roles for this gene in filamentous actin (F-actin) organization and cell division but its physiologic functions in mammals have not been investigated. Here we report that homozygous inactivation of Bin3 in the mouse causes cataracts and an increased susceptibility to lymphomas during aging. The cataract phenotype was marked by multiple morphologic defects in lens fibers, including the development of vacuoles in cortical fibers and a near total loss of F-actin in lens fiber cells but not epithelial cells. Through 1 year of age, no other phenotypes were apparent; however, by 18 months of age, Bin3−/− mice exhibited a significantly increased incidence of lymphoma. Bin3 loss did not affect normal cell proliferation, F-actin organization, or susceptibility to oncogenic transformation. In contrast, it increased the proliferation and invasive motility of cells transformed by SV40 large T antigen plus activated ras. Our findings establish functions for Bin3 in lens development and cancer suppression during aging. Further, they define Bin3 as a candidate for an unidentified tumor suppressor that exists at the human chromosome 8p21.3 locus. [Cancer Res 2008;68(6):1683–90]
Data from ERRγ Mediates Tamoxifen Resistance in Novel Models of Invasive Lobular Breast Cancer
Authors: Riggins Rebecca B. , Lan Jennifer P-J. , Klimach Uwe , Zwart Alan , Cavalli Luciane R. , Haddad Bassem R. , Chen Li , Gong Ting , Xuan Jianhua , Ethier Stephen P. , Clarke Robert
Published: March 2023

Abstract
One-third of all estrogen receptor (ER)–positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers each year and, whereas the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of ERα and increased expression of the estrogen-related receptor γ (ERRγ). Knockdown of ERRγ in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRγ blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRγ-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRγ/AP1 signaling in the development of TAM resistance and suggest that expression of ERRγ may be a marker of poor TAM response. [Cancer Res 2008;68(21):8908–17]
Data from DNA Methyltransferase 1 and 3B Activate BAG-1 Expression via Recruitment of CTCFL/BORIS and Modulation of Promoter Histone Methylation
Authors: Sun Lunching , Huang Lei , Nguyen Phuongmai , Bisht Kheem S. , Bar-Sela Gil , Ho Allen S. , Bradbury C. Matthew , Yu Wenqiang , Cui Hengmi , Lee Sunmin , Trepel Jane B. , Feinberg Andrew P. , Gius David
Published: March 2023

Abstract
In a previous genomic analysis, using somatic methyltransferase (DNMT) knockout cells, we showed that hypomethylation decreased the expression of as many genes as were observed to increase, suggesting a previously unknown mechanism for epigenetic regulation. To address this idea, the expression of the BAG family genes was used as a model. These genes were used because their expression was decreased in DNMT1−/−, DNMT3B−/−, and double knockout cells and increased in DNMT1-overexpressing and DNMT3B-overexpressing cells. Chromatin immunoprecipitation analysis of the BAG-1 promoter in DNMT1-overexpressing or DNMT3B-overexpressing cells showed a permissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status associated with DNA-binding of CTCFL/BORIS, as well as increased BAG-1 expression. In contrast, a nonpermissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status was associated with CTCF DNA-binding and decreased BAG-1 expression in the single and double DNMT knockout cells. BORIS short hairpin RNA knockdown decreased both promoter DNA-binding, as well as BAG-1 expression, and changed the dimethyl-H3-K4/dimethyl-H3-K9 ratio to that characteristic of a nonpermissive chromatin state. These results suggest that DNMT1 and DNMT3B regulate BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation. [Cancer Res 2008;68(8):2726–35]
Data from Silencing PinX1 Compromises Telomere Length Maintenance As Well As Tumorigenicity in Telomerase-Positive Human Cancer Cells
Authors: Zhang Bin , Bai Yun Xiu , Ma Hang Hang , Feng Feng , Jin Rui , Wang Zhi Long , Lin Jian , Sun Shi Peng , Yang Pingxun , Wang Xiao Xiong , Huang Pei Tang , Huang Cui Fen , Peng Ying , Chen Yang Chao , Kung Hsiang-fu , Huang Jun Jian
Published: March 2023

Abstract
The nucleolar protein PinX1 has been proposed to be a putative tumor suppressor due to its binding to and inhibition of the catalytic activity of telomerase, an enzyme that is highly expressed in most human cancers in which it counteracts telomere shortening–induced senescence to confer cancer cell immortalization. However, the role of PinX1 in telomere regulation, as well as in cancer, is still poorly understood. In this study, we showed that the PinX1 protein is constitutively expressed in various human cells regardless of their telomerase activity and malignant status. Most interestingly, we found that silencing PinX1 expression by a potent short hairpin RNA construct led to a robust telomere length shortening and growth inhibition in telomerase-positive but not in telomerase-negative human cancer cells. We further showed that silencing PinX1 significantly reduced the endogenous association of telomerase with the Pot1-containing telomeric protein complex, and therefore, could account for the phenotypic telomere shortening in the affected telomerase-positive cancer cells. Our results thus reveal a novel positive role for PinX1 in telomerase/telomere regulations and suggest that the constitutive expression of PinX1 attributes to telomere maintenance by telomerase and tumorigenicity in cancer cells. [Cancer Res 2009;69(1):75–83]
Data from Association of Autophagy Defect with a Malignant Phenotype and Poor Prognosis of Hepatocellular Carcinoma
Authors: Ding Zhen-Bin , Shi Ying-Hong , Zhou Jian , Qiu Shuang-Jian , Xu Yang , Dai Zhi , Shi Guo-Ming , Wang Xiao-Ying , Ke Ai-Wu , Wu Bin , Fan Jia
Published: March 2023

Abstract
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The role of autophagy and the prognostic value of autophagic genes are largely unknown in HCC. Here, we showed decreased expression of autophagic genes and their corresponding autophagic activity and increased expression of the antiapoptotic gene Bcl-xL in HCC cell lines compared with a normal hepatic cell line. We also found decreased expression of the autophagic gene Beclin 1 in 44 HCC tissue samples compared with adjacent nontumor tissues. In addition, we found that the most aggressive malignant HCC cell lines and HCC tissues with recurrent disease displayed much lower autophagic levels, especially when Bcl-xL was overexpressed. Interestingly, in a tissue microarray study consisting of 300 HCC patients who underwent curative resection, the expression of Beclin 1 was only significantly correlated with disease-free survival (DFS; P < 0.0001) and overall survival (OS; P < 0.0001) in the Bcl-xL+ group. Multivariate and univariate analyses also revealed that Beclin 1 expression was an independent predictor for DFS and OS in Bcl-xL+ patients. In addition, we found a significant correlation between Beclin 1 expression and tumor differentiation in Bcl-xL+ but not in Bcl-xL− HCC patients. In conclusion, our data showed expression of autophagic genes and their corresponding autophagic activities were suppressed in HCC. The autophagy defects synergized with altered apoptotic activity might facilitate tumor malignant differentiation, which results in a more aggressive cancer cell phenotype and poor prognosis of HCC. [Cancer Res 2008;68(22):9167–75]
Data from ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
Authors: Tse Christin , Shoemaker Alexander R. , Adickes Jessica , Anderson Mark G. , Chen Jun , Jin Sha , Johnson Eric F. , Marsh Kennan C. , Mitten Michael J. , Nimmer Paul , Roberts Lisa , Tahir Stephen K. , Xiao Yu , Yang Xiufen , Zhang Haichao , Fesik Stephen , Rosenberg Saul H. , Elmore Steven W.
Published: March 2023

Abstract
Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Ki's of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens. [Cancer Res 2008;68(9):3421–8]