bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table 3 from Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2
Authors: Wang Rui , Liu Hongwei , Shao Yingying , Wang Kailong , Yin Shuangshuang , Qiu Yuling , Wu Honghua , Liu Erwei , Wang Tao , Gao Xiumei , Yu Haiyang
Published: April 2023

Main pharmacokinetic parameters of Sophoridine after injection of caudal vein in rats
Supplementary Data from PTPN11 Plays Oncogenic Roles and Is a Therapeutic Target for BRAF Wild-Type Melanomas
Authors: Hill Kristen S. , Roberts Evan R. , Wang Xue , Marin Ellen , Park Taeeun D. , Son Sorany , Ren Yuan , Fang Bin , Yoder Sean , Kim Sungjune , Wan Lixin , Sarnaik Amod A. , Koomen John M. , Messina Jane L. , Teer Jamie K. , Kim Youngchul , Wu Jie , Chalfant Charles E. , Kim Minjung
Published: April 2023

Supplementary information and data, Supplementary figures 1-14
Supplementary Figures legends, and Supplementary Tables from FLYWCH1, a Novel Suppressor of Nuclear β-Catenin, Regulates Migration and Morphology in Colorectal Cancer
Authors: Muhammad Belal A. , Almozyan Sheema , Babaei-Jadidi Roya , Onyido Emenike K. , Saadeddin Anas , Kashfi Seyed Hossein , Spencer-Dene Bradley , Ilyas Mohammad , Lourdusamy Anbarasu , Behrens Axel , Nateri Abdolrahman S.
Published: April 2023

This file contains Supplementary Figures 1-9 legends, and Supplementary Tables 1 & 2.
Supplementary Figure Legends from p53 Function Is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma
Authors: Wei Yun , Maximov Victor , Morrissy Sorana A. , Taylor Michael D. , Pallas David C. , Kenney Anna Marie
Published: April 2023

Supplementary Figure Legends
Supplementary Methods, Figures 1 - 18 from Mechanochemical Disruption Suppresses Metastatic Phenotype and Pushes Prostate Cancer Cells toward Apoptosis
Authors: Murad Hakm Y. , Yu Heng , Luo Daishen , Bortz Emma P. , Halliburton Gray M. , Sholl Andrew B. , Khismatullin Damir B.
Published: April 2023

Supplementary Methods, Figures 1-18
Figure S4 from FLYWCH1, a Novel Suppressor of Nuclear β-Catenin, Regulates Migration and Morphology in Colorectal Cancer
Authors: Muhammad Belal A. , Almozyan Sheema , Babaei-Jadidi Roya , Onyido Emenike K. , Saadeddin Anas , Kashfi Seyed Hossein , Spencer-Dene Bradley , Ilyas Mohammad , Lourdusamy Anbarasu , Behrens Axel , Nateri Abdolrahman S.
Published: April 2023

S4. FLYWCH1 compete with TCF4 for binding to Tcf-DNA-binding elements in a beta-catenin dependent manner
Supplementary Figure 3 from MYC-Driven Tumorigenesis Is Inhibited by WRN Syndrome Gene Deficiency
Authors: Moser Russell , Toyoshima Masafumi , Robinson Kristin , Gurley Kay E. , Howie Heather L. , Davison Jerry , Morgan Martin , Kemp Christopher J. , Grandori Carla
Published: April 2023

PDF file - 502K
Supplementary Table 1 from The Th9 Axis Reduces the Oxidative Stress and Promotes the Survival of Malignant T Cells in Cutaneous T-Cell Lymphoma Patients
Authors: Kumar Sushant , Dhamija Bhavuk , Marathe Soumitra , Ghosh Sarbari , Dwivedi Alka , Karulkar Atharva , Sharma Neha , Sengar Manju , Sridhar Epari , Bonda Avinash , Thorat Jayashree , Tembhare Prashant , Shet Tanuja , Gujral Sumeet , Bagal Bhausaheb , Laskar Siddhartha , Jain Hasmukh , Purwar Rahul
Published: April 2023

Supplementary table S1: Follow-up patient's clinical details
Supplementary Figure 3 from Reduced DICER1 Elicits an Interferon Response in Endometrial Cancer Cells
Authors: Chiappinelli Katherine B. , Haynes Brian C. , Brent Michael R. , Goodfellow Paul J.
Published: April 2023

PDF file - 78K
Supplementary Figure 12 from SOX9 Is Essential for Triple-Negative Breast Cancer Cell Survival and Metastasis
Authors: Ma Yanxia , Shepherd Jonathan , Zhao Dekuang , Bollu Lakshmi Reddy , Tahaney William M. , Hill Jamal , Zhang Yun , Mazumdar Abhijit , Brown Powel H.
Published: April 2023

SOX9 controls EMT pathway
Supplementary Table 2 from Analysis of Gene Expression Regulated by the ETV5 Transcription Factor in OV90 Ovarian Cancer Cells Identifies FOXM1 Overexpression in Ovarian Cancer
Authors: Llauradó Marta , Majem Blanca , Castellví Josep , Cabrera Sílvia , Gil-Moreno Antonio , Reventós Jaume , Ruiz Anna
Published: April 2023

PDF file - 25K, Clinicopathological description of ovarian tumor samples used for quantitative PCR analysis of FoxM1 and ETV5
Supplementary Data from Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis
Authors: Phipps Laura E. , Hino Satoshi , Muschel Ruth J.
Published: April 2023

Supplementary Figures S1-S2.
Supplementary Figures 1-3 from Proteolytic Activation of Pro-Macrophage-Stimulating Protein by Hepsin
Authors: Ganesan Rajkumar , Kolumam Ganesh A. , Lin S. Jack , Xie Ming-Hong , Santell Lydia , Wu Thomas D. , Lazarus Robert A. , Chaudhuri Amitabha , Kirchhofer Daniel
Published: April 2023

PDF file - 504K
Supplementary Figures 1-4, Tables 1-6 from Mutational and Functional Analysis Reveals ADAMTS18 Metalloproteinase as a Novel Driver in Melanoma
Authors: Wei Xiaomu , Prickett Todd D. , Viloria Cristina G. , Molinolo Alfredo , Lin Jimmy C. , Cardenas-Navia Isabel , Cruz Pedro , Rosenberg Steven A. , Davies Michael A. , Gershenwald Jeffrey E. , López-Otín Carlos , Samuels Yardena
Published: April 2023

PDF file - 431K
Supplementary Table 1 from IKKβ Overexpression Leads to Pathologic Lesions in Stratified Epithelia and Exocrine Glands and to Tumoral Transformation of Oral Epithelia
Authors: Page Angustias , Cascallana José L. , Casanova M. Llanos , Navarro Manuel , Alameda Josefa P. , Pérez Paloma , Bravo Ana , Ramírez Angel
Published: April 2023

PDF file - 18K, Reproductive performance of K5-IKK� Tg female mice.
Supplementary Figure 6 from Adaptive Basal Phosphorylation of eIF2α Is Responsible for Resistance to Cellular Stress–Induced Cell Death in Pten-Null Hepatocytes
Authors: Zeng Ni , Li Yang , He Lina , Xu Xiaoling , Galicia Vivian , Deng Chuxia , Stiles Bangyan L.
Published: April 2023

PDF file - 1.0MB
Supplementary Figure Legends 1-3 from Ablation of Sphingosine Kinase-2 Inhibits Tumor Cell Proliferation and Migration
Authors: Gao Peng , Smith Charles D.
Published: April 2023

PDF file - 73K
Supplementary Figures S1-S4 from Loss of miR-200c Expression Induces an Aggressive, Invasive, and Chemoresistant Phenotype in Non–Small Cell Lung Cancer
Authors: Ceppi Paolo , Mudduluru Giridhar , Kumarswamy Regalla , Rapa Ida , Scagliotti Giorgio V. , Papotti Mauro , Allgayer Heike
Published: April 2023

Supplementary Figures S1-S4.
Supplementary Movie S2 from Critical Role of Endogenous Heme Oxygenase 1 as a Tuner of the Invasive Potential of Prostate Cancer Cells
Authors: Gueron Geraldine , De Siervi Adriana , Ferrando Mercedes , Salierno Marcelo , De Luca Paola , Elguero Belen , Meiss Roberto , Navone Nora , Vazquez Elba S.
Published: April 2023

Supplementary Movie S2 from Critical Role of Endogenous Heme Oxygenase 1 as a Tuner of the Invasive Potential of Prostate Cancer Cells
Data from Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade
Authors: Williams Michelle M. , Lee Linus , Hicks Donna J. , Joly Meghan M. , Elion David , Rahman Bushra , McKernan Courtney , Sanchez Violeta , Balko Justin M. , Stricker Thomas , Estrada Monica Valeria , Cook Rebecca S.
Published: April 2023

Abstract
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα+ tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα+ breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured in situ using Mcl-1/Bim proximity ligation assays. Importantly, MCL1 gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of BCL2 or BCL2L1 and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1–selective inhibitors for targeted tumor cell killing.

Implications: Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. Mol Cancer Res; 15(3); 259–68. ©2016 AACR.
Data from Gene Silencing Associated with SWI/SNF Complex Loss during NSCLC Development
Authors: Song Shujie , Walter Vonn , Karaca Mehmet , Li Ying , Bartlett Christopher S. , Smiraglia Dominic J. , Serber Daniel , Sproul Christopher D. , Plass Christoph , Zhang Jiren , Hayes D. Neil , Zheng Yanfang , Weissman Bernard E.
Published: April 2023

Abstract
The SWI/SNF chromatin-remodeling complex regulates gene expression and alters chromatin structures in an ATP-dependent manner. Recent sequencing efforts have shown mutations in BRG1 (SMARCA4), one of two mutually exclusive ATPase subunits in the complex, in a significant number of human lung tumor cell lines and primary non–small cell lung carcinoma (NSCLC) clinical specimens. To determine how BRG1 loss fuels tumor progression in NSCLC, molecular profiling was performed after restoration of BRG1 expression or treatment with a histone deacetylase inhibitor or a DNA methyltransferase (DNMT) inhibitor in a BRG1-deficient NSCLC cells. Importantly, validation studies from multiple cell lines revealed that BRG1 reexpression led to substantial changes in the expression of CDH1, CDH3, EHF, and RRAD that commonly undergo silencing by other epigenetic mechanisms during NSCLC development. Furthermore, treatment with DNMT inhibitors did not restore expression of these transcripts, indicating that this common mechanism of gene silencing did not account for their loss of expression. Collectively, BRG1 loss is an important mechanism for the epigenetic silencing of target genes during NSCLC development.

Implications: Inactivation of the SWI/SNF complex provides a novel mechanism to induce gene silencing during NSCLC development. Mol Cancer Res; 12(4); 560–70. ©2014 AACR.
Data from PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis
Authors: Gutierrez-Uzquiza Alvaro , Lopez-Haber Cynthia , Jernigan Danielle L. , Fatatis Alessandro , Kazanietz Marcelo G.
Published: April 2023

Abstract
The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCϵ), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCϵ expression was silenced using shRNA. Interestingly, while PKCϵ depletion had only marginal effects on the proliferative, adhesive, and migratory capacities of PC3-ML cells in vitro or in the growth of xenografts upon s.c. inoculation, it caused a significant reduction in cell invasiveness. Notably, PKCϵ was required for transendothelial cell migration (TEM) as well as for the growth of PC3-ML cells in a bone biomimetic environment. At a mechanistic level, PKCϵ depletion abrogates the expression of IL1β, a cytokine implicated in skeletal metastasis. Taken together, PKCϵ is a key factor for driving the formation of bone metastasis by prostate cancer cells and is a potential therapeutic target for advanced stages of the disease.

Implications: This study uncovers an important new function of PKCϵ in the dissemination of cancer cells to the bone; thus, highlighting the promising potential of this oncogenic kinase as a therapeutic target for skeletal metastasis. Mol Cancer Res; 13(9); 1336–46. ©2015 AACR.
Data from The Adherens Junction Protein Afadin Is an AKT Substrate that Regulates Breast Cancer Cell Migration
Authors: Elloul Sivan , Kedrin Dmitriy , Knoblauch Nicholas W. , Beck Andrew H. , Toker Alex
Published: April 2023

Abstract
The PI3K–AKT signaling pathway regulates all phenotypes that contribute to progression of human cancers, including breast cancer. AKT mediates signal relay by phosphorylating numerous substrates, which are causally implicated in biologic responses such as cell growth, survival, metabolic reprogramming, migration, and invasion. Here a new AKT substrate is identified, the adherens junction protein Afadin, which is phosphorylated by AKT at Ser1718. Importantly, under conditions of physiologic IGF-1 signaling and oncogenic PI3K and AKT, Afadin is phosphorylated by all AKT isoforms, and this phosphorylation elicits a relocalization of Afadin from adherens junctions to the nucleus. Also, phosphorylation of Afadin increased breast cancer cell migration that was dependent on Ser1718 phosphorylation. Finally, nuclear localization of Afadin was observed in clinical breast cancer specimens, indicating that regulation of Afadin by the PI3K–AKT pathway has pathophysiologic significance.

Implications: Phosphorylation of the adhesion protein Afadin by AKT downstream of the PI3K pathway, leads to redistribution of Afadin and controls cancer cell migration. Mol Cancer Res; 12(3); 464–76. ©2013 AACR.
Data from Increased Expression of System xc− in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance
Authors: Polewski Monika D. , Reveron-Thornton Rosyli F. , Cherryholmes Gregory A. , Marinov Georgi K. , Cassady Kaniel , Aboody Karen S.
Published: April 2023

Abstract
Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system xc−, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc− in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc− with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system xc− in glioma, stable SLC7A11-knockdown and -overexpressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but overexpression did increase anchorage-independent cell growth. Knockdown of SLC7A11 increased basal reactive oxygen species (ROS) and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Overexpression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 overexpression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation, and ATP generation. These results suggest that expression of SLC7A11 in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy.

Implications: SLC7A11, in addition to redox modulation, appears to be associated with increased cellular metabolism and is a mediator of temozolomide resistance in human glioma, thus making system xC− a potential therapeutic target in glioblastoma multiforme. Mol Cancer Res; 14(12); 1229–42. ©2016 AACR.
Data from A Novel EGFR Extracellular Domain Mutant, EGFRΔ768, Possesses Distinct Biological and Biochemical Properties in Neuroblastoma
Authors: Keller James , Nimnual Anjaruwee S. , Varghese Mathew S. , VanHeyst Kristen A. , Hayman Michael J. , Chan Edward L.
Published: April 2023

Abstract
EGFR is a popular therapeutic target for many cancers. EGFR inhibitors have been tested in children with refractory neuroblastoma. Interestingly, partial response or stable disease was observed in a few neuroblastoma patients. As EGFR mutations are biomarkers for response to anti-EGFR drugs, primary neuroblastoma tumors and cell lines were screened for mutations. A novel EGFR extracellular domain deletion mutant, EGFRΔ768, was discovered and the biologic and biochemical properties of this mutant were characterized and compared with wild-type and EGFRvIII receptors. EGFRΔ768 was found to be constitutively active and localized to the cell surface. Its expression conferred resistance to etoposide and drove proliferation as well as invasion of cancer cells. While EGFRΔ768 had similarity to EGFRvIII, its biologic and biochemical properties were distinctly different from both the EGFRvIII and wild-type receptors. Even though erlotinib inhibited EGFRΔ768, its effect on the mutant was not as strong as that on wild-type EGFR and EGFRvIII. In addition, downstream signaling of EGFRΔ768 was different from that of the wild-type receptor. In conclusion, this is the first study to demonstrate that neuroblastoma express not only EGFRvIII, but also a novel EGFR extracellular domain deletion mutant, EGFRΔ768. The EGFRΔ768 also possesses distinct biologic and biochemical properties which might have therapeutic implications for neuroblastoma as well as other tumors expressing this novel mutant.

Implications: Neuroblastoma expressed a novel EGFR mutant which possesses distinct biologic and biochemical properties that might have therapeutic implications. Mol Cancer Res; 14(8); 740–52. ©2016 AACR.
Data from Targeted Deletion and Lipidomic Analysis Identify Epithelial Cell COX-2 as a Major Driver of Chemically Induced Skin Cancer
Authors: Jiao Jing , Ishikawa Tomo-O , Dumlao Darren S. , Norris Paul C. , Magyar Clara E. , Mikulec Carol , Catapang Art , Dennis Edward A. , Fischer Susan M. , Herschman Harvey R.
Published: April 2023

Abstract
Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX-2) plays a critical role in DMBA/TPA–induced skin tumor induction. Although many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell type–specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell–specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell–specific Cox-2 gene deletion, compared with littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2–expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA–treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2–dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell type–specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biologic responses.

Implications:Cox-2 gene deletion demonstrates that intrinsic COX-2 expression in initiated keratinocytes is a principal driver of skin carcinogenesis; lipidomic analysis identifies likely prostanoid effectors. Mol Cancer Res; 12(11); 1677–88. ©2014 AACR.
Data from HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis
Authors: Janeckova Lucie , Pospichalova Vendula , Fafilek Bohumil , Vojtechova Martina , Tureckova Jolana , Dobes Jan , Dubuissez Marion , Leprince Dominique , Baloghova Nikol , Horazna Monika , Hlavata Adela , Stancikova Jitka , Sloncova Eva , Galuskova Katerina , Strnad Hynek , Korinek Vladimir
Published: April 2023

Abstract
Hypermethylated in cancer 1 (HIC1) represents a prototypic tumor suppressor gene frequently inactivated by DNA methylation in many types of solid tumors. The gene encodes a sequence-specific transcriptional repressor controlling expression of several genes involved in cell cycle or stress control. In this study, a Hic1 allele was conditionally deleted, using a Cre/loxP system, to identify genes influenced by the loss of Hic1. One of the transcripts upregulated upon Hic1 ablation is the toll-like receptor 2 (TLR2). Tlr2 expression levels increased in Hic1-deficient mouse embryonic fibroblasts (MEF) and cultured intestinal organoids or in human cells upon HIC1 knockdown. In addition, HIC1 associated with the TLR2 gene regulatory elements, as detected by chromatin immunoprecipitation, indicating that Tlr2 indeed represents a direct Hic1 target. The Tlr2 receptor senses “danger” signals of microbial or endogenous origin to trigger multiple signaling pathways, including NF-κB signaling. Interestingly, Hic1 deficiency promoted NF-κB pathway activity not only in cells stimulated with Tlr2 ligand, but also in cells treated with NF-κB activators that stimulate different surface receptors. In the intestine, Hic1 is mainly expressed in differentiated epithelial cells and its ablation leads to increased Tlr2 production. Finally, in a chemical-induced mouse model of carcinogenesis, Hic1 absence resulted in larger Tlr2-positive colonic tumors that showed increased proportion of proliferating cells.

Implications: The tumor-suppressive function of Hic1 in colon is related to its inhibitory action on proproliferative signaling mediated by the Tlr2 receptor present on tumor cells. Mol Cancer Res; 13(7); 1139–48. ©2015 AACR.
Data from Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model
Authors: Balestrini Alessia , Nicolas Laura , Yang-lott Katherine , Guryanova Olga A. , Levine Ross L. , Bassing Craig H. , Chaudhuri Jayanta , Petrini John H.J.
Published: April 2023

Abstract
The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATMflox) was crossed to hypomorphic NBS1 mutants (Nbs1ΔB/ΔB mice). Nbs1ΔB/ΔB Atm−/− hematopoietic cells derived by crossing to vavcre were viable in vivo. Nbs1ΔB/ΔB Atm−/− VAV mice exhibited a pronounced defect in double-strand break repair and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress in vivo. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress.

Implications: A novel mouse model was developed, by combining a vavcre-inducible ATM knockout mouse with an NBS1 hypomorphic mutation, to analyze ATM-independent functions of the Mre11 complex in vivo. These data show that the DNA repair, rather than DDR signaling functions of the complex, is acutely required in the context of ATM deficiency to suppress genome instability and lymphomagenesis. Mol Cancer Res; 14(2); 185–95. ©2015 AACR.
Data from Actin-Binding Protein, Espin: A Novel Metastatic Regulator for Melanoma
Authors: Yanagishita Takeshi , Yajima Ichiro , Kumasaka Mayuko , Kawamoto Yoshiyuki , Tsuzuki Toyonori , Matsumoto Yoshinari , Watanabe Daisuke , Kato Masashi
Published: April 2023

Abstract
Espin is a multifunctional actin-bundling protein with multiple isoforms, and has special connections to hair cell stereocilia and microvillar specializations of sensory cells in the inner ear. However, there have been no reports showing the expression and function of Espin in cancers, including melanoma. Here, it is demonstrated that Espin expression is significantly increased in melanomas that spontaneously developed in RET-transgenic mice (RET-mice). Importantly, the invasion capacity of Espin-depleted Mel-ret melanoma cells derived from a tumor of the RET-mouse was dramatically less than that of control melanoma cells with reductions of lamellipodia, focal adhesion kinase (FAK), and GTP-Rac1 activities. Correspondingly, the ratio of metastatic foci in Espin-depleted Mel-ret melanoma cells was significantly less than that of control melanoma cells in an in vivo melanoma metastasis model. Moreover, Espin could be a novel biomarker of melanoma in humans, because our immunohistochemical analysis data reveal that percentages of Espin-positive cells in human primary and metastatic melanomas were significantly higher than that of cells in melanocytic nevi. Together, these results indicate that Espin is not only a metastatic regulator for melanoma but also a potential biomarker of disease progression.

Implications: Actin-binding protein Espin is expressed in melanoma, affects metastasis, and is a potential target for melanoma therapy. Mol Cancer Res; 12(3); 440–6. ©2013 AACR.
Data from AMPK Causes Cell Cycle Arrest in LKB1-Deficient Cells via Activation of CAMKK2
Authors: Fogarty Sarah , Ross Fiona A. , Vara Ciruelos Diana , Gray Alexander , Gowans Graeme J. , Hardie D. Grahame
Published: April 2023

Abstract
The AMP-activated protein kinase (AMPK) is activated by phosphorylation at Thr172, either by the tumor suppressor kinase LKB1 or by an alternate pathway involving the Ca2+/calmodulin-dependent kinase, CAMKK2. Increases in AMP:ATP and ADP:ATP ratios, signifying energy deficit, promote allosteric activation and net Thr172 phosphorylation mediated by LKB1, so that the LKB1–AMPK pathway acts as an energy sensor. Many tumor cells carry loss-of-function mutations in the STK11 gene encoding LKB1, but LKB1 reexpression in these cells causes cell-cycle arrest. Therefore, it was investigated as to whether arrest by LKB1 is caused by activation of AMPK or of one of the AMPK-related kinases, which are also dependent on LKB1 but are not activated by CAMKK2. In three LKB1-null tumor cell lines, treatment with the Ca2+ ionophore A23187 caused a G1 arrest that correlated with AMPK activation and Thr172 phosphorylation. In G361 cells, expression of a truncated, Ca2+/calmodulin-independent CAMKK2 mutant also caused G1 arrest similar to that caused by expression of LKB1, while expression of a dominant-negative AMPK mutant, or a double knockout of both AMPK-α subunits, also prevented the cell-cycle arrest caused by A23187. These mechanistic findings confirm that AMPK activation triggers cell-cycle arrest, and also suggest that the rapid proliferation of LKB1-null tumor cells is due to lack of the restraining influence of AMPK. However, cell-cycle arrest can be restored by reexpressing LKB1 or a constitutively active CAMKK2, or by pharmacologic agents that increase intracellular Ca2+ and thus activate endogenous CAMKK2.

Implications: Evidence here reveals that the rapid growth and proliferation of cancer cells lacking the tumor suppressor LKB1 is due to reduced activity of AMPK, and suggests a therapeutic approach by which this block might be circumvented. Mol Cancer Res; 14(8); 683–95. ©2016 AACR.
Data from Role for the Aryl Hydrocarbon Receptor and Diverse Ligands in Oral Squamous Cell Carcinoma Migration and Tumorigenesis
Authors: Stanford Elizabeth A. , Ramirez-Cardenas Alejandra , Wang Zhongyan , Novikov Olga , Alamoud Khalid , Koutrakis Petros , Mizgerd Joseph P. , Genco Caroline A. , Kukuruzinska Maria , Monti Stefano , Bais Manish V. , Sherr David H.
Published: April 2023

Abstract
Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AhR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AhR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AhR activity in two oral squamous cell lines was modulated with AhR prototypic, environmental and bacterial AhR ligands, AhR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: (i) primary OSCC tissue expresses elevated levels of nuclear AhR as compared with normal tissue, (ii) AhR mRNA expression is upregulated in 320 primary OSCCs, (iii) AhR hyperactivation with several ligands, including environmental and bacterial ligands, significantly increases AhR activity, ALDH1 activity, and accelerates cell migration, (iv) AhR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, (v) AhR knockdown inhibits tumorsphere formation in low adherence conditions, and (vi) AhR knockdown inhibits tumor growth and increases overall survival in vivo. These data demonstrate that the AhR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental, and bacterial AhR ligands may exacerbate OSCC by enhancing expression of these properties.

Implications: This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro. Mol Cancer Res; 14(8); 696–706. ©2016 AACR.
Data from Glucose-6–phosphatase Is a Key Metabolic Regulator of Glioblastoma Invasion
Authors: Abbadi Sara , Rodarte Julio J. , Abutaleb Ameer , Lavell Emily , Smith Chris L. , Ruff William , Schiller Jennifer , Olivi Alessandro , Levchenko Andre , Guerrero-Cazares Hugo , Quinones-Hinojosa Alfredo
Published: April 2023

Abstract
Glioblastoma (GBM) remains the most aggressive primary brain cancer in adults. Similar to other cancers, GBM cells undergo metabolic reprogramming to promote proliferation and survival. Glycolytic inhibition is widely used to target such reprogramming. However, the stability of glycolytic inhibition in GBM remains unclear especially in a hypoxic tumor microenvironment. In this study, it was determined that glucose-6–phosphatase (G6PC/G6Pase) expression is elevated in GBM when compared with normal brain. Human-derived brain tumor–initiating cells (BTIC) use this enzyme to counteract glycolytic inhibition induced by 2-deoxy-d-glucose (2DG) and sustain malignant progression. Downregulation of G6PC renders the majority of these cells unable to survive glycolytic inhibition, and promotes glycogen accumulation through the activation of glycogen synthase (GYS1) and inhibition of glycogen phosphorylase (PYGL). Moreover, BTICs that survive G6PC knockdown are less aggressive (reduced migration, invasion, proliferation, and increased astrocytic differentiation). Collectively, these findings establish G6PC as a key enzyme with promalignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target.

Implications: This study is the first to demonstrate a functional relationship between the critical gluconeogenic and glycogenolytic enzyme G6PC with the metabolic adaptations during GBM invasion.

Visual Overview: http://mcr.aacrjournals.org/content/12/11/1547/F1.large.jpg.

Mol Cancer Res; 12(11); 1547–59. ©2014 AACR.
Data from An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma
Authors: Lavorato-Rocha Andre M. , Akagi Erica M. , de Melo Maia Beatriz , Rodrigues Iara S. , Botelho Mayara Caroline Silva , Marchi Fabio A. , Fernandes Gabriel , Baiocchi Glauco , Soares Fernando A. , Rogatto Silvia Regina , Sato-Kuwabara Yukie , Rocha Rafael M.
Published: April 2023

Abstract
Vulvar squamous cell carcinoma (VSCC) is a rare disease that has a high mortality rate (∼40%). However, little is known about its molecular signature. Therefore, an integrated genomics approach, based on comparative genome hybridization (aCGH) and genome-wide expression (GWE) array, was performed to identify driver genes in VSCC. To achieve that, DNA and RNA were extracted from frozen VSCC clinical specimens and examined by aCGH and GWE array, respectively. On the basis of the integration of data using the CONEXIC algorithm, PLXDC2 and GNB3 were validated by RT-qPCR. The expression of these genes was then analyzed by IHC in a large set of formalin-fixed paraffin-embedded specimens. These analyses identified 47 putative drivers, 46 of which were characterized by copy number gains that were concomitant with overexpression and one with a copy number loss and downregulation. Two of these genes, PLXDC2 and GNB3, were selected for further validation: PLXDC2 was downregulated and GNB3 was overexpressed compared with non-neoplastic tissue. By IHC, both proteins were ubiquitously expressed throughout vulvar tissue. High expression of GNB3 and low PLXDC2 immunostaining in the same sample was significantly associated with less lymph node metastasis and greater disease-free survival. On the basis of a robust methodology never used before for VSCC evaluation, two novel prognostic markers in vulvar cancer are identified: one with favorable prognosis (GNB3) and the other with unfavorable prognosis (PLXDC2).

Implications: This genomics study reveals markers that associate with prognosis and may provide guidance for better treatment in vulvar cancer. Mol Cancer Res; 14(8); 720–9. ©2016 AACR.
Data from A New Role for ERα: Silencing via DNA Methylation of Basal, Stem Cell, and EMT Genes
Authors: Ariazi Eric A. , Taylor John C. , Black Michael A. , Nicolas Emmanuelle , Slifker Michael J. , Azzam Diana J. , Boyd Jeff
Published: April 2023

Abstract
Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α–positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+ cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERα expression, and resuppressed by gain of ERα activity/expression. ERα-dependent DNA methylation targets (n = 39) were enriched for ERα-binding sites, basal-up/luminal-down markers, cancer stem cell, epithelial–mesenchymal transition, and inflammatory and tumor suppressor genes. Kaplan–Meier survival curve and Cox proportional hazards regression analyses indicated that these targets predicted poor distant metastasis–free survival among a large cohort of breast cancer patients. The basal breast cancer subtype markers LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites. Thus, genes that are methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.

Implications: ERα directs DNA methylation–mediated silencing of specific genes that have biomarker potential in breast cancer subtypes. Mol Cancer Res; 15(2); 152–64. ©2016 AACR.
Data from Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis
Authors: Reaves Denise K. , Hoadley Katherine A. , Fagan-Solis Katerina D. , Jima Dereje D. , Bereman Michael , Thorpe Lynnelle , Hicks Jyla , McDonald David , Troester Melissa A. , Perou Charles M. , Fleming Jodie M.
Published: April 2023

Abstract
Lipolysis-stimulated lipoprotein receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacologic manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Coimmunoprecipitation and proximal ligation assays indicated LSR–pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that overexpress LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes.

Implications: LSR functions in the promotion of aggressive breast cancer phenotypes and poor patient outcome via differential subcellular localization to alter cell signaling, bioenergetics, and gene expression. Mol Cancer Res; 15(2); 165–78. ©2016 AACR.
Data from Intrinsic Resistance to Cixutumumab Is Conferred by Distinct Isoforms of the Insulin Receptor
Authors: Forest Amelie , Amatulli Michael , Ludwig Dale L. , Damoci Christopher B. , Wang Ying , Burns Colleen A. , Donoho Gregory P. , Zanella Nina , Fiebig Heinz H. , Prewett Marie C. , Surguladze David , DeLigio James T. , Houghton Peter J. , Smith Malcolm A. , Novosiadly Ruslan
Published: April 2023

Abstract
Despite a recent shift away from anti–insulin-like growth factor I receptor (IGF-IR) therapy, this target has been identified as a key player in the resistance mechanisms to various conventional and targeted agents, emphasizing its value as a therapy, provided that it is used in the right patient population. Molecular markers predictive of antitumor activity of IGF-IR inhibitors remain largely unidentified. The aim of this study is to evaluate the impact of insulin receptor (IR) isoforms on the antitumor efficacy of cixutumumab, a humanized mAb against IGF-IR, and to correlate their expression with therapeutic outcome. The data demonstrate that expression of total IR rather than individual IR isoforms inversely correlates with single-agent cixutumumab efficacy in pediatric solid tumor models in vivo. Total IR, IR-A, and IR-B expression adversely affects the outcome of cixutumumab in combination with chemotherapy in patient-derived xenograft models of lung adenocarcinoma. IR-A overexpression in tumor cells confers complete resistance to cixutumumab in vitro and in vivo, whereas IR-B results in a partial resistance. Resistance in IR-B–overexpressing cells is fully reversed by anti–IGF-II antibodies, suggesting that IGF-II is a driver of cixutumumab resistance in this setting. The present study links IR isoforms, IGF-II, and cixutumumab efficacy mechanistically and identifies total IR as a biomarker predictive of intrinsic resistance to anti–IGF-IR antibody.

Implications: This study identifies total IR as a biomarker predictive of primary resistance to IGF-IR antibodies and provides a rationale for new clinical trials enriched for patients whose tumors display low IR expression. Mol Cancer Res; 13(12); 1615–26. ©2015 AACR.
Data from AMPKα2 Regulates Bladder Cancer Growth through SKP2-Mediated Degradation of p27
Authors: Kopsiaftis Stavros , Sullivan Katie L. , Garg Isha , Taylor John A. , Claffey Kevin P.
Published: April 2023

Abstract
AMP-activated protein kinase (AMPK) is the central metabolic regulator of the cell and controls energy consumption based upon nutrient availability. Due to its role in energy regulation, AMPK has been implicated as a barrier for cancer progression and is suppressed in multiple cancers. To examine whether AMPK regulates bladder cancer cell growth, HTB2 and HT1376 bladder cells were treated with an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). AICAR treatment reduced proliferation and induced the expression of p27Kip1 (CDKN1B), which was mediated through an mTOR-dependent mechanism. Interestingly, AMPKα2 knockdown resulted in reduced p27 levels, whereas AMPKα1 suppression did not. To further determine the exact mechanism by which AMPKa2 regulates p27, HTB2 and HT1376 cells were transduced with an shRNA targeting AMPKα2. Stable knockdown of AMPKα2 resulted in increased proliferation and decreased p27 protein. The reduced p27 protein was determined to be dependent upon SKP2. Additionally, loss of AMPKα2 in a xenograft and a chemical carcinogen model of bladder cancer resulted in larger tumors with less p27 protein and high SKP2 levels. Consistent with the regulation observed in the bladder cancer model systems, a comprehensive survey of human primary bladder cancer clinical specimens revealed low levels of AMPKα2 and p27 and high levels of SKP2.

Implications: These results highlight the contribution of AMPKα2 as a mechanism for controlling bladder cancer growth by regulating proliferation through mTOR suppression and induction of p27 protein levels, thus indicating how AMPKα2 loss may contribute to tumorigenesis. Mol Cancer Res; 14(12); 1182–94. ©2016 AACR.
Data from P-Cadherin Promotes Ovarian Cancer Dissemination Through Tumor Cell Aggregation and Tumor–Peritoneum Interactions
Authors: Usui Akihiro , Ko Song Yi , Barengo Nicolas , Naora Honami
Published: April 2023

Abstract
More than 60% of patients who are diagnosed with epithelial ovarian cancer (EOC) present with extensive peritoneal carcinomatosis. EOC cells typically disseminate by shedding into the peritoneal fluid in which they survive as multicellular aggregates and then implant onto peritoneal surfaces. However, the mechanism that facilitates aggregation and implantation of EOC cells is poorly understood. The cell adhesion molecule P-cadherin has been reported to be induced during early progression of EOC and to promote tumor cell migration. In this study, P-cadherin not only promoted migration of EOC cells, but also facilitated the assembly of floating EOC cells into multicellular aggregates and inhibited anoikis in vitro. Furthermore, inhibiting P-cadherin by short hairpin RNAs (shRNA) or a neutralizing antibody prevented EOC cells from attaching to peritoneal mesothelial cells in vitro. In mouse intraperitoneal xenograft models of EOC, inhibition of P-cadherin decreased the aggregation and survival of floating tumor cells in ascites and reduced the number of tumor implants on peritoneal surfaces. These findings indicate that P-cadherin promotes intraperitoneal dissemination of EOC by facilitating tumor cell aggregation and tumor–peritoneum interactions in addition to promoting tumor cell migration.

Implications: Inhibiting P-cadherin blocks multiple key steps of EOC progression and has therapeutic potential. Mol Cancer Res; 12(4); 504–13. ©2014 AACR.
Data from Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation
Authors: Hassani Zahra , Saleh Ali , Turpault Soumaya , Khiati Salim , Morelle Willy , Vignon Jacques , Hugnot Jean-Philippe , Uro-Coste Emmanuelle , Legrand Philippe , Delaforge Marcel , Loiseau Séverine , Clarion Ludovic , Lecouvey Marc , Volle Jean-Noël , Virieux David , Pirat Jean-Luc , Duffau Hugues , Bakalara Norbert
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFβR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial–mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. Mol Cancer Res; 15(10); 1376–87. ©2017 AACR.
Data from SIRT1 Inactivation Evokes Antitumor Activities in NSCLC through the Tumor Suppressor p27
Authors: Zhu Lijia , Chiao Christine Y. , Enzer Katelyn G. , Stankiewicz Alexander J. , Faller Douglas V. , Dai Yan
Published: April 2023

Abstract
P27Kip1 (CDKN1B) regulates cellular proliferation and senescence, and p27Kip1 deficiency in cancer is strongly correlated with poor prognosis of multiple cancer types. Understanding the mechanism of p27Kip1 loss in cancer and the consequences of restoring p27Kip1 levels is therefore critical for effective management during therapy. Here, SIRT1, a class III histone deacetylase (HDAC), is identified as an important regulator of p27Kip1 expression. Mechanistically, SIRT1 reduces p27Kip1 expression by decreasing p27Kip1 protein stability through the ubiquitin–proteasome pathway. In addition, SIRT1 silencing suppresses non–small cell lung cancer (NSCLC) proliferation and induces senescence in a p27Kip1-dependent manner. Furthermore, SIRT1 silencing dramatically suppresses tumor formation and proliferation in two distinct NSCLC xenograft mouse models. Collectively, these data demonstrate that not only SIRT1 is an important regulator of p27Kip1 but also SIRT inhibition induces senescence and antigrowth potential in lung cancer in vivo.

Implications: SIRT1 is a key regulator of p27 protein levels and SIRT1 inhibition is a viable strategy for NSCLC therapy by means of p27 reactivation. Mol Cancer Res; 13(1); 41–49. ©2014 AACR.