bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S6 from PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
Authors: Long Li-Li , Ma Si-Cong , Guo Ze-Qin , Zhang Yan-Pei , Fan Zhenzhen , Liu Li-Juan , Liu Li , Han Duan-Duan , Leng Meng-Xin , Wang Jian , Guo Xue-Jun , Tan Jia-Le , Cai Xiao-Ting , Lin Yan , Pan Xinghua , Wu De-Hua , Bai Xue , Dong Zhong-Yi
Published: March 2023

Anti-PD-1/olaparib treatment promotes IFNγ secretion by CD8+ T cells in the tumor microenvironment. Mice-bearing orthotopic lung tumors were treated with different therapies. Representative IHC stainings of IFNγ expression in tumor tissues were shown. Scale bar, 50 μm.The right graph showed the IHC statistical analysis of IFNγ expression in tumor tissues. n = 5 fields from independent tumors. Data are represented as mean ± SD; Student's t-tests; **P<0.01; ***P<0.001; ****P<0.0001; ns, not significant.
Figure S1 from Estimation of Neutral Mutation Rates and Quantification of Somatic Variant Selection Using cancereffectsizeR
Authors: Mandell Jeffrey D. , Cannataro Vincent L. , Townsend Jeffrey P.
Published: March 2023

Supplementary Figure 1
Supplementary Data from Stimulated Raman Scattering Microscopy Enables Gleason Scoring of Prostate Core Needle Biopsy by a Convolutional Neural Network
Authors: Ao Jianpeng , Shao Xiaoguang , Liu Zhijie , Liu Qiang , Xia Jun , Shi Yongheng , Qi Lin , Pan Jiahua , Ji Minbiao
Published: March 2023

Supplementary information
Supplementary table S2 from SMAD4 Loss Induces c-MYC–Mediated NLE1 Upregulation to Support Protein Biosynthesis, Colorectal Cancer Growth, and Metastasis
Authors: Loevenich Leon P. , Tschurtschenthaler Markus , Rokavec Matjaz , Silva Miguel G. , Jesinghaus Moritz , Kirchner Thomas , Klauschen Frederick , Saur Dieter , Neumann Jens , Hermeking Heiko , Jung Peter
Published: March 2023

RNA Seq_count matrix
Supplementary Data from SMAD4 Loss Induces c-MYC–Mediated NLE1 Upregulation to Support Protein Biosynthesis, Colorectal Cancer Growth, and Metastasis
Authors: Loevenich Leon P. , Tschurtschenthaler Markus , Rokavec Matjaz , Silva Miguel G. , Jesinghaus Moritz , Kirchner Thomas , Klauschen Frederick , Saur Dieter , Neumann Jens , Hermeking Heiko , Jung Peter
Published: March 2023

Supplementary Figures S1-5
S1: Effect of SMAD4 loss on intestinal stem cell, c-MYC, and NLE1 gene expression in CRC organoids
S2: Effects of NLE1 ablation on growth and clonogenicity of CRC cell lines
S3: Effects of NLE1 ablation on growth and clonogenicity of CRC PDTOs
S4: Effects of NLE1 over-expression in human colonic epithelial cells and CRC organoids
S5: NLE1 loss-mediated cell cycle arrest and apoptosis in HCT116 CRC cells and HCEC-1CT normal human colonic epithelial cells
Supplementary Data from PINK1-Mediated Mitophagy Promotes Oxidative Phosphorylation and Redox Homeostasis to Induce Drug-Tolerant Persister Cancer Cells
Authors: Li Yun , Chen Hengxing , Xie Xuan , Yang Bing , Wang Xiaojuan , Zhang Jingyuan , Qiao Tian , Guan Jiao , Qiu Yuntan , Huang Yong-Xin , Tian Duanqing , Yao Xinyi , Lu Daning , Koeffler H. Phillip , Zhang Yin , Yin Dong
Published: March 2023

Figures S1-S12;Tables S1-S4
All Supplemental Data Except Supplemental Tables S3 and S4 from Spatial Transcriptomic Analysis of Ovarian Cancer Precursors Reveals Reactivation of IGFBP2 during Pathogenesis
Authors: Wang Yeh , Huang Peng , Wang Brant G. , Murdock Tricia , Cope Leslie , Hsu Fang-Chi , Wang Tian-Li , Shih Ie-Ming
Published: March 2023

Supplemental Materials, Supplemental Tables S1, S2,and S5, Supplemental Figures S1-S6
Supplementary Fig-7 from The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
Authors: Gambi Giovanni , Mengus Gabrielle , Davidson Guillaume , Demesmaeker Ewout , Cuomo Alessandro , Bonaldi Tiziana , Katopodi Vicky , Malouf Gabriel G. , Leucci Eleonora , Davidson Irwin
Published: March 2023

LENOX and RAP2C knockdown induce mitochondrial dysfunction, release of reactive oxygen species (ROS), DNA damage and cell cycle block
Supplementary Fig-2 from The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
Authors: Gambi Giovanni , Mengus Gabrielle , Davidson Guillaume , Demesmaeker Ewout , Cuomo Alessandro , Bonaldi Tiziana , Katopodi Vicky , Malouf Gabriel G. , Leucci Eleonora , Davidson Irwin
Published: March 2023

LENOX regulates melanoma cell proliferation and survival
Table ST6 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

Table ST6: Differential expressed lipids and their FDRs in sensitive vs resistant cells (negative values are upregulated in sensitive cells).
Table ST3 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

Table ST3: Differential expressed RNA transcripts between MEKi-sensitive and -resistant melanoma cell cultures.
Suppl. Figure S7 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

S7: Pathway enrichment (metabolomics)
Suppl. Figure S14 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

S14: CCLE cancer cell panel analysis for the responses to neocuproine
Suppl Figure S4 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

S4: Neocuproine is a copper-dependent ROS inducer
Data from Class III β-Tubulin Mediates Sensitivity to Chemotherapeutic Drugs in Non–Small Cell Lung Cancer
Authors: Gan Pei Pei , Pasquier Eddy , Kavallaris Maria
Published: March 2023

Abstract
First line therapy for non–small cell lung carcinoma (NSCLC) commonly includes combination therapy with a tubulin-binding agent (TBA) and a DNA-damaging agent. TBAs suppress microtubule dynamics by binding to the β-tubulin subunit of α/β-tubulin, inducing mitotic arrest and apoptosis. Up-regulation of class III β-tubulin (βIII-tubulin) has been implicated in clinical resistance in NSCLC, ovarian and breast tumors treated in combination with a TBA and DNA-damaging agent. To investigate the functional significance of βIII-tubulin in resistance to both these classes of agents, small interfering RNA (siRNA) was used to silence the expression of this isotype in two NSCLC cell lines, NCI-H460 and Calu-6. Reverse transcription-PCR and immunoblotting showed that βIII-siRNA potently inhibited the expression of βIII-tubulin, without affecting the expression of other major β-tubulin isotypes. Clonogenic assays showed that βIII-siRNA cells were significantly more sensitive to TBAs, paclitaxel, vincristine, and vinorelbine, and for the first time, DNA-damaging agents, cisplatin, doxorubicin, and etoposide compared with controls. Cell cycle analysis of H460 βIII-siRNA cells showed reduced accumulation at the G2-M boundary and an increase in the sub-G1 population in response to TBA treatment compared with control cells. Importantly, βIII-siRNA cells displayed a significant dose-dependent increase in Annexin V staining when treated with either paclitaxel or cisplatin, compared with controls. These findings have revealed a novel role for βIII-tubulin in mediating response to both TBA and DNA-damaging agent therapy and may have important implications for improving the targeting and treatment of drug-refractory NSCLC. [Cancer Res 2007;67(19):9356–63]
Data from Targeted Overexpression of Vav3 Oncogene in Prostatic Epithelium Induces Nonbacterial Prostatitis and Prostate Cancer
Authors: Liu Yin , Mo Jun Qin , Hu Qiande , Boivin Gregory , Levin Linda , Lu Shan , Yang Dianer , Dong Zhongyun
Published: March 2023

Abstract
Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor (AR), and stimulates growth in prostate cancer cells. The purpose of this study is to further determine the potential role of Vav3 in prostate cancer development in genetically engineered mouse model. We generated Vav3 transgenic mice by targeted overexpression of a constitutive active Vav3 in the prostatic epithelium. We found that overexpression of Vav3 led to development of mouse prostatic intraepithelial neoplasia and prostate cancer at the age of as early as 3 months. The AR signaling axis and phosphatidylinositol 3-kinase-Akt signaling were elevated in the prostate glands of Vav3 transgenic mice. In addition to prostate cancer, Vav3 transgenic mice developed significant nonbacterial chronic prostatitis in the prostate gland with notable infiltration of lymphomononuclear cells (monocytes, lymphocytes, and plasma cells), which was associated with elevated incidence of prostate cancer. DNA microarray and signaling pathway analysis revealed that the top diseases and disorders were inflammatory diseases and cancer of the prostate gland in Vav3 transgenic mice. In vitro analysis showed that overexpression of Vav3 in prostate cancer cells enhanced nuclear factor-κB (NF-κB) activity, implicating an underlying mechanism of innate inflammatory response induced by elevated Vav3 activity. These data showed that Vav3 overexpression in the prostate epithelium enhanced both the AR signaling axis and NF-κB–mediated pathway, which potentially contributed to the development of nonbacterial prostatitis and prostate cancer. [Cancer Res 2008;68(15):6396–406]
Data from Salmonella Promoters Preferentially Activated Inside Tumors
Authors: Arrach Nabil , Zhao Ming , Porwollik Steffen , Hoffman Robert M. , McClelland Michael
Published: March 2023

Abstract
Salmonella enterica and avirulent derivatives prefer solid tumors over normal tissue in animal models. The identification of endogenous Salmonella promoters that are preferentially activated in tumors could further our understanding of this phenomenon. Toward this goal, a random library of S. enterica typhimurium 14028 genomic DNA was cloned upstream of a promoterless gene encoding the green fluorescent protein (GFP) TurboGFP. A population of Salmonella containing this library was injected i.v. into tumor-free nude mice and into human PC3 prostate tumors growing subcutaneously in nude mice. After 2 days, fluorescence-activated cell sorting was used to enrich for bacterial clones expressing GFP from spleens or tumors. The resulting libraries were hybridized to an oligonucleotide tiling array of the Salmonella genome. Eighty-six intergenic regions were found to be enriched in tumor samples but not in spleen. Twenty of these candidate promoters were also detected in the sequences of 100 random clones from a library enriched for expression in bacteria growing in tumors. Three candidate promoter clones were individually tested in vivo, and enhanced GFP expression in bacteria growing in tumor relative to spleen was confirmed. Two of the three clones (pflE and ansB promoter regions) are known to be induced in hypoxic conditions that pertain to many tumors. For many of the other candidate promoters preferentially induced in bacteria growing in tumors, regulatory mechanisms may not be related to hypoxia. The expression of therapeutics in Salmonella under the regulation of one or more promoters that are activated preferentially in tumors has the potential to improve the targeting of drug delivery. [Cancer Res 2008;68(12):4827–32]
Data from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers
Authors: Rebbeck Timothy R. , Mitra Nandita , Domchek Susan M. , Wan Fei , Chuai Shannon , Friebel Tara M. , Panossian Saarene , Spurdle Amanda , Chenevix-Trench Georgia , Singer Christian F. , Pfeiler Georg , Neuhausen Susan L. , Lynch Henry T. , Garber Judy E. , Weitzel Jeffrey N. , Isaacs Claudine , Couch Fergus , Narod Steven A. , Rubinstein Wendy S. , Tomlinson Gail E. , Ganz Patricia A. , Olopade Olufunmilayo I. , Tung Nadine , Blum Joanne L. , Greenberg Roger , Nathanson Katherine L. , Daly Mary B.
Published: March 2023

Abstract
Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]
Data from Epigallocatechin-3-Gallate, a Histone Acetyltransferase Inhibitor, Inhibits EBV-Induced B Lymphocyte Transformation via Suppression of RelA Acetylation
Authors: Choi Kyung-Chul , Jung Myung Gu , Lee Yoo-Hyun , Yoon Joo Chun , Kwon Seung Hyun , Kang Hee-Bum , Kim Mi-Jeong , Cha Jeong-Heon , Kim Young Jun , Jun Woo Jin , Lee Jae Myun , Yoon Ho-Geun
Published: March 2023

Abstract
Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-κB (NF-κB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 μmol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IκBα, and suppresses tumor necrosis factor α (TNFα)–induced NF-κB activation. We also showed that EGCG prevents TNFα-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-κB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-κB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-κB–mediated inflammatory signaling pathway. Importantly, EGCG at 50 μmol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases. [Cancer Res 2009;69(2):583–92]
Data from Kinome Profiling in Pediatric Brain Tumors as a New Approach for Target Discovery
Authors: Sikkema Arend H. , Diks Sander H. , den Dunnen Wilfred F.A. , ter Elst Arja , Scherpen Frank J.G. , Hoving Eelco W. , Ruijtenbeek Rob , Boender Piet J. , de Wijn Rik , Kamps Willem A. , Peppelenbosch Maikel P. , de Bont Eveline S.J.M.
Published: March 2023

Abstract
Progression in pediatric brain tumor growth is thought to be the net result of signaling through various protein kinase-mediated networks driving cell proliferation. Defining new targets for treatment of human malignancies, without a priori knowledge on aberrant cell signaling activity, remains exceedingly complicated. Here, we introduce kinome profiling using flow-through peptide microarrays as a new concept for target discovery. Comprehensive tyrosine kinase activity profiles were identified in 29 pediatric brain tumors using the PamChip kinome profiling system. Previously reported activity of epidermal growth factor receptor, c-Met, and vascular endothelial growth factor receptor in pediatric brain tumors could be appreciated in our array results. Peptides corresponding with phosphorylation consensus sequences for Src family kinases showed remarkably high levels of phosphorylation compared with normal tissue types. Src activity was confirmed applying Phos-Tag SDS-PAGE. Furthermore, the Src family kinase inhibitors PP1 and dasatinib induced substantial tumor cell death in nine pediatric brain tumor cell lines but not in control cell lines. Thus, this study describes a new high-throughput technique to generate clinically relevant tyrosine kinase activity profiles as has been shown here for pediatric brain tumors. In the era of a rapidly increasing number of small-molecule inhibitors, this approach will enable us to rapidly identify new potential targets in a broad range of human malignancies. [Cancer Res 2009;69(14):5987–95]
Data from NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development
Authors: Izumchenko Eugene , Singh Mahendra K. , Plotnikova Olga V. , Tikhmyanova Nadezhda , Little Joy L. , Serebriiskii Ilya G. , Seo Sachiko , Kurokawa Mineo , Egleston Brian L. , Klein-Szanto Andres , Pugacheva Elena N. , Hardy Richard R. , Wolfson Marina , Connolly Denise C. , Golemis Erica A.
Published: March 2023

Abstract
In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9−/− mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9+/+ and Nedd9−/− tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness. [Cancer Res 2009;69(18):7198–206]
Data from Epithelial-to-Mesenchymal Transition and Resistance to Ingenol 3-Angelate, a Novel Protein Kinase C Modulator, in Colon Cancer Cells
Authors: Ghoul Aïda , Serova Maria , Astorgues-Xerri Lucile , Bieche Ivan , Bousquet Guilhem , Varna Mariana , Vidaud Michel , Phillips Edelmira , Weill Sophie , Benhadji Karim A. , Lokiec François , Cvitkovic Esteban , Faivre Sandrine , Raymond Eric
Published: March 2023

Abstract
Acquired resistance to protein kinase C (PKC) modulators may explain the failure of clinical trials in patients with cancer. Herein, we established a human colon cancer cell line resistant to PEP005, a drug that inhibits PKCα and activates PKCδ. Colo205-R cells, selected by stepwise exposure to PEP005, were >300-fold more resistant to PEP005 than parental Colo205-S cells and were cross-resistant to phorbol 12-myristate 13-acetate, bryostatin, bistratene A, and staurosporine. No PKCα or PKCδ mutation was detected in Colo205-S and Colo205-R cells. Changes in Colo205-R cells were reminiscent of the epithelial-to-mesenchymal transition (EMT) phenotype. Accordingly, Colo205-R cells were more invasive than Colo205-S in Matrigel assays and in mouse xenografts. We also found an increased mRNA expression of several EMT genes, such as those encoding for transforming growth factor-β and vimentin, along with a decreased mRNA expression of genes involved in epithelial differentiation, such as CDH1 (E-cadherin), CLDN4 (claudin 4), S100A4, and MUC1, in Colo205-R compared with Colo205-S cells in vitro and in vivo. Interestingly, high expression of ET-1 was shown in Colo205-R cells and correlated with low sensitivity to PEP005 and staurosporine in a panel of 10 human cancer cell lines. Inhibition of the ET-1 receptor ETR-A with bosentan restored the antiproliferative effects of PEP005 in Colo205-R cells and decreased the invasive properties of this cell line. Exogenous exposure to ET-1 and silencing ET-1 expression using small interfering RNA modulated cell signaling in Colo205-S and Colo205-R. In summary, acquired resistance to PEP005 was associated with expression of EMT markers and activates the ET-1/ETR-A cell signaling. [Cancer Res 2009;69(10):4260–69]
Data from The Decline in U.S. Cancer Mortality in People Born since 1925
Authors: Kort Eric J. , Paneth Nigel , Vande Woude George F.
Published: March 2023

Abstract
The conventional practice of analyzing overall age-adjusted cancer mortality rates heavily emphasizes the experience of older, higher mortality age groups. This may conceal shifts in lifetime cancer mortality experience emerging first in younger age groups. We examined age-specific cancer mortality rates and birth cohort–specific cancer mortality rates in U.S. mortality data recorded since 1955 to assess the effects of age, period, and cohort in secular mortality trends. Cancer mortality and population data were obtained from WHO Statistical Information System. Age-specific cancer mortality rates have been steadily declining in the United States since the early 1950s, beginning with children and young adults and now including all age groups. During the second half of the 20th century, each successive decade of births from 1925 to 1995 experienced a lower risk of cancer death than its predecessor at virtually every age for which such a comparison can be made. A major decline in cancer mortality has been occurring in the United States for the past 50 years, affecting birth cohorts born as long as 80 years ago. Excepting lung cancer, much of this decline has occurred despite relatively stable cancer incidence. These findings suggest that improvements in cancer detection, treatment, and/or prevention have reduced the risk of cancer death across the life span for individuals born in the last three quarters of the 20th century. [Cancer Res 2009;69(16):6500–5]
Data from Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21Cip1 in Cervical Carcinogenesis
Authors: Shin Myeong-Kyun , Balsitis Scott , Brake Tiffany , Lambert Paul F.
Published: March 2023

Abstract
The E7 oncoprotein of the high-risk human papillomaviruses (HPV) is thought to contribute to cervical carcinogenesis at least in part by abrogating cell cycle regulation. E7 can dysregulate the cell cycle through its interaction with several cellular proteins including the retinoblastoma suppressor protein pRb, as well as the cyclin-dependent kinase inhibitor p21Cip1. Inactivation of pRb in cervical epithelia is not sufficient to explain the ability of E7 to cause cervical cancers in transgenic mice. In the current study, we focused on the role of p21Cip1 in cervical cancer. Cervical disease was significantly increased in p21−/− mice compared with p21+/+ mice, showing that p21Cip1 can function as a tumor suppressor in this tissue. Importantly, the ability of E7 to induce cervical cancers was not significantly enhanced on the p21-null background, consistent with the hypothesis that the ability of E7 to inhibit p21Cip1 contributes to its carcinogenic properties. Further supportive of this hypothesis, cervical carcinogenesis in mice expressing a mutant form of HPV-16 E7, E7CVQ, which fails to inactivate p21Cip1, was significantly reduced compared with that in K14E7WT mice expressing wild-type HPV-16 E7. However, K14E7CVQ mice still displayed heightened levels of cervical carcinogenesis compared with that in nontransgenic mice, indicating that activities of E7 besides its capacity to inactivate p21Cip1 also contribute to cervical carcinogenesis. Taken together, we conclude that p21Cip1 functions as a tumor suppressor in cervical carcinogenesis and that p21Cip1 inactivation by HPV-16 E7 partially contributes to the contribution of E7 to cervical carcinogenesis. [Cancer Res 2009;69(14):5656–63]
Data from Complex Oncogenic Translocations with Gene Amplification Are Initiated by Specific DNA Breaks in Lymphocytes
Authors: Wright Sarah M. , Woo Yong H. , Alley Travis L. , Shirley Bobbi-Jo , Akeson Ellen C. , Snow Kathy J. , Maas Sarah A. , Elwell Rachel L. , Foreman Oded , Mills Kevin D.
Published: March 2023

Abstract
Chromosomal instability is a hallmark of many tumor types. Complex chromosomal rearrangements with associated gene amplification, known as complicons, characterize many hematologic and solid cancers. Whereas chromosomal aberrations, including complicons, are useful diagnostic and prognostic cancer markers, their molecular origins are not known. Although accumulating evidence has implicated DNA double-strand break repair in suppression of oncogenic genome instability, the genomic elements required for chromosome rearrangements, especially complex lesions, have not been elucidated. Using a mouse model of B-lineage lymphoma, characterized by complicon formation involving the immunoglobulin heavy chain (Igh) locus and the c-myc oncogene, we have now investigated the requirement for specific genomic segments as donors for complex rearrangements. We now show that specific DNA double-strand breaks, occurring within a narrow segment of Igh, are necessary to initiate complicon formation. By contrast, neither specific DNA breaks nor the powerful intronic enhancer Eμ are required for complicon-independent oncogenesis. This study is the first to delineate mechanisms of complex versus simple instability and the first to identify specific chromosomal elements required for complex chromosomal aberrations. These findings will illuminate genomic cancer susceptibility and risk factors. [Cancer Res 2009;69(10):4454–60]
Data from Genome-Wide Identification of Direct Target Genes Implicates Estrogen-Related Receptor α as a Determinant of Breast Cancer Heterogeneity
Authors: Deblois Geneviève , Hall Jacqueline A. , Perry Marie-Claude , Laganière Josée , Ghahremani Majid , Park Morag , Hallett Michael , Giguère Vincent
Published: March 2023

Abstract
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERRα shares functional features with the estrogen receptor α (ERα) and its activity is modulated by the ERBB2 signaling pathway. Using genome-wide binding sites location analyses in ERα-positive and ERα-negative breast cancer cell lines, we show that ERRα and ERα display strict binding site specificity and maintain independent mechanisms of transcriptional activation. Nonetheless, ERRα and ERα coregulate a small subset of common target genes via binding either to a dual-specificity binding site or to distinct cognate binding sites located within the extended promoter region of the gene. Although ERRα signaling in breast cancer cells is mostly independent of ERα, the small fraction of common ERRα/ERα targets comprises genes with high relevance to breast tumor biology, including genes located within the ERBB2 amplicon and GATA3. Finally, unsupervised hierarchical clustering based on the expression profiling of ERRα direct target genes in human breast tumors revealed four main clusters that recapitulate established tumor subtypes. Taken together, the identification and functional characterization of the ERRα transcriptional network implicate ERRα signaling as a determinant of breast cancer heterogeneity. [Cancer Res 2009;69(15):6149–57]
Data from A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition
Authors: Pampalakis Georgios , Prosnikli Evangelia , Agalioti Theodora , Vlahou Antonia , Zoumpourlis Vassilis , Sotiropoulou Georgia
Published: March 2023

Abstract
Human kallikrein-related peptidase 6 (KLK6) was cloned as a putative class II tumor suppressor based on its inactivated expression in metastatic breast cancer. Here, we investigated the mechanism(s) underlying the silencing of KLK6 gene in metastatic breast cancer and its putative implications for tumor progression. We present evidence that tumor-specific loss of KLK6 expression is due to hypermethylation of specific CpGs located in the KLK6 proximal promoter. Methylation-dependent binding of methyl CpG-binding protein 2 and the formation of repressive chromatin mediated by localized histone deacetylation are critical components of KLK6 silencing in breast tumors. Re-expression of KLK6 in nonexpressing MDA-MB-231 breast tumor cells by stable cDNA transfection resulted in marked reversal of their malignant phenotype, manifested by lower proliferation rates and saturation density, marked inhibition of anchorage-independent growth, reduced cell motility, and their dramatically reduced ability to form tumors when implanted in severe combined immunodeficiency mice. Interestingly, inhibition of tumor growth was observed at physiologic concentrations of KLK6, but not when KLK6 was highly overexpressed, as observed in a subset of breast tumors. Differential proteomic profiling revealed that KLK6 re-expression results in significant down-regulation of vimentin which represents an established marker of epithelial-to-mesenchymal transition of tumor cells and in concomitant up-regulation of calreticulin and epithelial markers cytokeratin 8 and 19, indicating that KLK6 may play a protective role against tumor progression that is likely mediated by inhibition of epithelial-to-mesenchymal transition. We suggest that KLK6 is an epigenetically regulated tumor suppressor in human breast cancer and provide ways of pharmacologic modulation. [Cancer Res 2009;69(9):3779–87]
Data from A Requirement for Cyclin-Dependent Kinase 6 in Thymocyte Development and Tumorigenesis
Authors: Hu Miaofen G. , Deshpande Amit , Enos Miriam , Mao Daqin , Hinds Elisabeth A. , Hu Guo-fu , Chang Rui , Guo Zhuyan , Dose Marei , Mao Changchuin , Tsichlis Philip N. , Gounari Fotini , Hinds Philip W.
Published: March 2023

Abstract
Cyclin-dependent kinase 6 (CDK6) promotes cell cycle progression and is overexpressed in human lymphoid malignancies. To determine the role of CDK6 in development and tumorigenesis, we generated and analyzed knockout mice. Cdk6-deficient mice show pronounced thymic atrophy due to reduced proliferative fractions and concomitant transitional blocks in the double-negative stages. Using the OP9-DL1 system to deliver temporally controlled Notch receptor–dependent signaling, we show that CDK6 is required for Notch-dependent survival, proliferation, and differentiation. Furthermore, CDK6-deficient mice were resistant to lymphomagenesis induced by active Akt, a downstream target of Notch signaling. These results show a critical requirement for CDK6 in Notch/Akt-dependent T-cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies. [Cancer Res 2009;69(3):810–8]
Data from Surface-Immobilized Aptamers for Cancer Cell Isolation and Microscopic Cytology
Authors: Wan Yuan , Kim Young-tae , Li Na , Cho Steve K. , Bachoo Robert , Ellington Andrew D. , Iqbal Samir M.
Published: March 2023

Abstract
Exposing rare but highly malignant tumor cells that migrate from the primary tumor mass into adjacent tissue(s) or circulate in the bloodstream is critical for early detection and effective intervention(s). Here, we report on an aptamer-based strategy directed against epidermal growth factor receptor (EGFR), the most common oncogene in glioblastoma (GBM), to detect these deadly tumor cells. GBMs are characterized by diffuse infiltration into normal brain regions, and the inability to detect GBM cells renders the disease surgically incurable with a median survival of just 14.2 months. To test the sensitivity and specificity of our platform, anti-EGFR RNA aptamers were immobilized on chemically modified glass surfaces. Cells tested included primary human GBM cells expressing high levels of the wild-type EGFR, as well as genetically engineered murine glioma cells overexpressing the most common EGFR mutant (EGFRvIII lacking exons 2–7) in Ink4a/Arf-deficient astrocytes. We found that surfaces functionalized with anti-EGFR aptamers could capture both the human and murine GBM cells with high sensitivity and specificity. Our findings show how novel aptamer substrates could be used to determine whether surgical resection margins are free of tumor cells, or more widely for detecting tumor cells circulating in peripheral blood to improve early detection and/or monitoring residual disease after treatment. Cancer Res; 70(22); 9371–80. ©2010 AACR.
Data from GP369, an FGFR2-IIIb–Specific Antibody, Exhibits Potent Antitumor Activity against Human Cancers Driven by Activated FGFR2 Signaling
Authors: Bai Ailin , Meetze Kristan , Vo Nhi Y. , Kollipara Sriram , Mazsa Elizabeth K. , Winston William M. , Weiler Solly , Poling Laura L. , Chen Ting , Ismail Nesreen S. , Jiang Jinwei , Lerner Lorena , Gyuris Jeno , Weng Zhigang
Published: March 2023

Abstract
Dysregulated fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of human cancers. Aberrant activation of FGF receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification, has been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand-binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We surveyed a broad panel of human cancer cell lines for the dysregulation of FGFR2 signaling and discovered that breast and gastric cancer cell lines harboring FGFR2 amplification predominantly express the IIIb isoform of the receptor. Therefore, we used an FGFR2-IIIb–specific antibody, GP369, to investigate the importance of FGFR2 signaling in vitro and in vivo. GP369 specifically and potently suppressed ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support the hypothesis that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies. Cancer Res; 70(19); 7630–9. ©2010 AACR.
Data from A Novel Method of Transcriptional Response Analysis to Facilitate Drug Repositioning for Cancer Therapy
Authors: Jin Guangxu , Fu Changhe , Zhao Hong , Cui Kemi , Chang Jenny , Wong Stephen T.C.
Published: March 2023

Abstract
Little research has been done to address the huge opportunities that may exist to reposition existing approved or generic drugs for alternate uses in cancer therapy. In addition, there has been little work on strategies to reposition experimental cancer agents for testing in alternate settings that could shorten their clinical development time. Progress in each area has lagged, in part, because of the lack of systematic methods to define drug off-target effects (OTE) that might affect important cancer cell signaling pathways. In this study, we addressed this critical gap by developing an OTE-based method to repurpose drugs for cancer therapeutics, based on transcriptional responses made in cells before and after drug treatment. Specifically, we defined a new network component called cancer-signaling bridges (CSB) and integrated it with a Bayesian factor regression model (BFRM) to form a new hybrid method termed CSB-BFRM. Proof-of-concept studies were conducted in breast and prostate cancer cells and in promyelocytic leukemia cells. In each system, CSB-BFRM analysis could accurately predict clinical responses to more than 90% of drugs approved by the U.S. Food and Drug Administration and more than 75% of experimental clinical drugs that were tested. Mechanistic investigation of OTEs for several high-ranking drug–dose pairs suggested repositioning opportunities for cancer therapy, based on the ability to enforce retinoblastoma-dependent repression of important E2F-dependent cell-cycle genes. Together, our findings establish new methods to identify opportunities for drug repositioning or to elucidate the mechanisms of action of repositioned drugs. Cancer Res; 72(1); 33–44. ©2011 AACR.
Data from Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment
Authors: Isaacs John T. , Antony Lizamma , Dalrymple Susan L. , Brennen W. Nathaniel , Gerber Stephanie , Hammers Hans , Wissing Michel , Kachhap Sushant , Luo Jun , Xing Li , Björk Per , Olsson Anders , Björk Anders , Leanderson Tomas
Published: March 2023

Abstract
Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10–30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1α, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386–99. ©2012 AACR.
Data from Animal Models of Human Prostate Cancer: The Consensus Report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee
Authors: Ittmann Michael , Huang Jiaoti , Radaelli Enrico , Martin Philip , Signoretti Sabina , Sullivan Ruth , Simons Brian W. , Ward Jerrold M. , Robinson Brian D. , Chu Gerald C. , Loda Massimo , Thomas George , Borowsky Alexander , Cardiff Robert D.
Published: March 2023

Abstract
Animal models, particularly mouse models, play a central role in the study of the etiology, prevention, and treatment of human prostate cancer. While tissue culture models are extremely useful in understanding the biology of prostate cancer, they cannot recapitulate the complex cellular interactions within the tumor microenvironment that play a key role in cancer initiation and progression. The National Cancer Institute (NCI) Mouse Models of Human Cancers Consortium convened a group of human and veterinary pathologists to review the current animal models of prostate cancer and make recommendations about the pathologic analysis of these models. More than 40 different models with 439 samples were reviewed, including genetically engineered mouse models, xenograft, rat, and canine models. Numerous relevant models have been developed over the past 15 years, and each approach has strengths and weaknesses. Analysis of multiple genetically engineered models has shown that reactive stroma formation is present in all the models developing invasive carcinomas. In addition, numerous models with multiple genetic alterations display aggressive phenotypes characterized by sarcomatoid carcinomas and metastases, which is presumably a histologic manifestation of epithelial–mesenchymal transition. The significant progress in development of improved models of prostate cancer has already accelerated our understanding of the complex biology of prostate cancer and promises to enhance development of new approaches to prevention, detection, and treatment of this common malignancy. Cancer Res; 73(9); 2718–36. ©2013 AACR.
Data from DNA Damage–Specific Control of Cell Death by Cryptochrome in p53-Mutant Ras–Transformed Cells
Authors: Lee Jin Hyup , Gaddameedhi Shobhan , Ozturk Nuri , Ye Rui , Sancar Aziz
Published: March 2023

Abstract
The main feedback loop driving circadian rhythm in mice is controlled, in part, by the genes encoding the cryptochromes Cry1 and Cry2. Targeted mutation of both Cry1 and Cry2 delay the early onset of tumor formation in p53-null mutant mice. Furthermore, Ras-transformed p53- and Cry-null mouse skin fibroblasts are more sensitive than p53 mutants to apoptotic cell death initiated by agents that activate either the intrinsic or the extrinsic apoptosis pathways. Here, we investigated the effect of Cry1 and Cry2 mutations on cell death by other genotoxic agents that generate alkylated bases, interstrand crosslinks, DNA–protein crosslinks, and double-strand breaks. Both ultraviolet (UV) and the UV mimetic compound oxaliplatin and the radiomimetic compound doxorubicin promoted apoptosis by upregulating the tumor suppressor p73. However, only the UV and oxaliplatin-induced upregulation of p73 mediated by the transcription factor Egr1, but not the doxorubicin-induced upregulation mediated by the transcription factor E2F1, was enhanced by Cry1/Cry2 double mutation. Accordingly, Egr1 downregulation reduced oxaliplatin-induced apoptosis, whereas E2F1 downregulation reduced doxorubicin-induced apoptosis. Our findings establish distinct roles for cryptochromes in intrinsic apoptosis induced by UV mimetic and radiomimetic agents. Cancer Res; 73(2); 785–91. ©2012 AACR.
Data from Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H
Authors: Kudo-Saito Chie , Yura Masahiro , Yamamoto Ryusuke , Kawakami Yutaka
Published: March 2023

Abstract
Human endogenous retroviruses (HERV) are associated with many diseases such as autoimmune diseases and cancer. Although the frequent expression of a variety of HERVs in tumor cells has been demonstrated, their functional contributions in cancer are as yet unclear. Intriguingly, HERVs and other retroviruses include an immunosuppressive domain in their transmembrane envelope proteins, but its mechanism of action and cancer relevance are obscure. In this study, we demonstrate that the human endogenous retrovirus HERV-H has a critical role in tumor metastasis and immune escape. We found that expression of herv-h mRNA was elevated in metastatic tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and in primary tumor tissues from advanced colon cancer. The immunosuppressive peptide H17 derived from HERV-H was sufficient to induce EMT in tumor cells that expressed low levels of HERV-H, and it amplified this event within the tumor microenvironment. H17 also stimulated CCL19 expression in tumor cells, which in turn recruited and expanded a population of pluripotent immunoregulatory CD271+ cells, which included mesenchymal stem cells and myeloid-derived suppressor cells. In tumor tissues from patients with advanced colon cancer, we confirmed that CD271+ cells were increased in HERV-H+CCL19+ tumor tissues. Notably, RNAi-mediated change of HERV-H or CCL19, or depletion of CD271+ cells, improved immune responses in vitro and in vivo accompanied by tumor regression. Together, our results argued that HERV-H is a critical determinant of immune escape in cancer, suggesting its candidacy as a promising therapeutic target to treat patients with advanced cancer. Cancer Res; 74(5); 1361–70. ©2014 AACR.