bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Oncogene AEG-1 Promotes Glioma-Induced Neurodegeneration by Increasing Glutamate Excitotoxicity
Authors: Lee Seok-Geun , Kim Keetae , Kegelman Timothy P. , Dash Rupesh , Das Swadesh K. , Choi Jung Kyoung , Emdad Luni , Howlett Eric L. , Jeon Hyun Yong , Su Zhao Zhong , Yoo Byoung Kwon , Sarkar Devanand , Kim Sung-Hoon , Kang Dong-Chul , Fisher Paul B.
Published: March 2024

Abstract
Aggressive tumor growth, diffuse tissue invasion, and neurodegeneration are hallmarks of malignant glioma. Although glutamate excitotoxicity is considered to play a key role in glioma-induced neurodegeneration, the mechanism(s) controlling this process is poorly understood. Astrocyte elevated gene-1 (AEG-1) is an oncogene that is overexpressed in several types of human cancers, including more than 90% of brain tumors. In addition, AEG-1 promotes gliomagenesis, particularly in the context of tumor growth and invasion, 2 primary characteristics of glioma. In the present study, we investigated the contribution of AEG-1 to glioma-induced neurodegeneration. Pearson correlation coefficient analysis in normal brain tissues and samples from glioma patients indicated a strong negative correlation between expression of AEG-1 and a primary glutamate transporter of astrocytes EAAT2. Gain- and loss-of-function studies in normal primary human fetal astrocytes and T98G glioblastoma multiforme cells revealed that AEG-1 repressed EAAT2 expression at a transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter. In addition, AEG-1–mediated EAAT2 repression caused a reduction of glutamate uptake by glial cells, resulting in induction of neuronal cell death. These findings were also confirmed in samples from glioma patients showing that AEG-1 expression negatively correlated with NeuN expression. Taken together, our findings suggest that AEG-1 contributes to glioma-induced neurodegeneration, a hallmark of this fatal tumor, through regulation of EAAT2 expression. Cancer Res; 71(20); 6514–23. ©2011 AACR.
Data from Nicotinamide Blocks Proliferation and Induces Apoptosis of Chronic Lymphocytic Leukemia Cells through Activation of the p53/miR-34a/SIRT1 Tumor Suppressor Network
Authors: Audrito Valentina , Vaisitti Tiziana , Rossi Davide , Gottardi Daniela , D'Arena Giovanni , Laurenti Luca , Gaidano Gianluca , Malavasi Fabio , Deaglio Silvia
Published: March 2024

Abstract
Because of its relatively indolent clinical course, chronic lymphocytic leukemia (CLL) offers a versatile model for testing novel therapeutic regimens and drug combinations. Nicotinamide is the main NAD+ precursor and a direct inhibitor of four classes of enzymes, including the sirtuins. SIRT1, the main member of the sirtuin family, inactivates p53 by deacetylating a critical lysine residue. In this study, we showed that CLL cells express high levels of functional SIRT1, which is inhibited by exogenous nicotinamide. This agent blocks proliferation and promotes apoptosis selectively in leukemic cells that express wild-type (wt) p53. Nicotinamide modulates the p53-dependent genes p21, NOXA, BAX, and Mcl-1, indicating an activation of the p53 pathway and of caspase-3. DNA-damaging chemotherapeutics, such as etoposide, activate a functional loop linking SIRT1 and p53 through the induction of miR-34a. When leukemic cells are simultaneously exposed to nicotinamide and etoposide, we observe a significant increase in miR-34a levels with a concomitant inhibition of SIRT1. Furthermore, p53 acetylation levels are higher than with either agent used alone. Overall, treatment with both nicotinamde and etoposide shows strongly synergistic effects in the induction of apoptosis. We therefore concluded that nicotinamide has the dual property of inhibiting SIRT1 through a noncompetitive enzymatic block (p53 independent) and at the same time through miR-34a induction (p53 dependent). These observations suggested the therapeutic potential of nicotinamide, a novel, safe, and inexpensive drug, to be used in addition to chemotherapy for CLL patients with wt p53. Cancer Res; 71(13); 4473–83. ©2011 AACR.
Data from A Unique Metastasis Gene Signature Enables Prediction of Tumor Relapse in Early-Stage Hepatocellular Carcinoma Patients
Authors: Roessler Stephanie , Jia Hu-Liang , Budhu Anuradha , Forgues Marshonna , Ye Qing-Hai , Lee Ju-Seog , Thorgeirsson Snorri S. , Sun Zhongtang , Tang Zhao-You , Qin Lun-Xiu , Wang Xin Wei
Published: March 2024

Abstract
Metastasis-related recurrence often occurs in hepatocellular carcinoma (HCC) patients who receive curative therapies. At present, it is challenging to identify patients with high risk of recurrence, which would warrant additional therapies. In this study, we sought to analyze a recently developed metastasis-related gene signature for its utility in predicting HCC survival, using 2 independent cohorts consisting of a total of 386 patients who received radical resection. Cohort 1 contained 247 predominantly HBV-positive cases analyzed with an Affymetrix platform, whereas cohort 2 contained 139 cases with mixed etiology analyzed with the NCI Oligo Set microarray platform. We employed a survival risk prediction algorithm with training, test, and independent cross-validation strategies and found that the gene signature is predictive of overall and disease-free survival. Importantly, risk was significantly predicted independently of clinical characteristics and microarray platform. In addition, survival prediction was successful in patients with early disease, such as small (<5 cm in diameter) and solitary tumors, and the signature predicted particularly well for early recurrence risk (<2 years), especially when combined with serum alpha fetoprotein or tumor staging. In conclusion, we have shown in 2 independent cohorts with mixed etiologies and ethnicity that the metastasis gene signature is a useful tool to predict HCC outcome, suggesting the general utility of this classifier. We recommend the use of this classifier as a molecular diagnostic test to assess the risk that an HCC patient will develop tumor relapse within 2 years after surgical resection, particularly for those with early-stage tumors and solitary presentation. Cancer Res; 70(24); 10202–12. ©2010 AACR.
Data from Novel Role for STAT3 in Transcriptional Regulation of NK Immune Cell Targeting Receptor MICA on Cancer Cells
Authors: Bedel Romain , Thiery-Vuillemin Antoine , Grandclement Camille , Balland Jeremy , Remy-Martin Jean-Paul , Kantelip Bernadette , Pallandre Jean-René , Pivot Xavier , Ferrand Christophe , Tiberghien Pierre , Borg Christophe
Published: March 2024

Abstract
The role of natural killer group 2, member D receptor (NKG2D)–expressing natural killer (NK) cells in tumor immunosurveillance is now well established. Nevertheless, tumor progression occurs despite tumor immunosurveillance, leading to cancer persistence in immunocompetent hosts. STAT3 plays a pivotal role both in oncogenic functions and in immunosuppression. In this study, we investigated the role of STAT3 in suppressing NK cell–mediated immunosurveillance. Using a colorectal cancer cell line (HT29) that can poorly activate NK, we neutralized STAT3 with pharmacologic inhibitors or siRNA and found that this led to an increase in NK degranulation and IFN-γ production in a TGF-β1–independent manner. Exposure to NKG2D-neutralizing antibodies partially restored STAT3 activity, suggesting that it prevented NKG2D-mediated NK cell activation. On this basis, we investigated the expression of NKG2D ligands after STAT3 activation in HT29, mesenchymal stem cells, and activated lymphocytes. The NK cell recognition receptor MHC class I chain–related protein A (MICA) was upregulated following STAT3 neutralization, and a direct interaction between STAT3 and the MICA promoter was identified. Because cross-talk between DNA damage repair and NKG2D ligand expression has been shown, we assessed the influence of STAT3 on MICA expression under conditions of genotoxic stress. We found that STAT3 negatively regulated MICA expression after irradiation or heat shock, including in lymphocytes activated by CD3/CD28 ligation. Together, our findings reveal a novel role for STAT3 in NK cell immunosurveillance by modulating the MICA expression in cancer cells. Cancer Res; 71(5); 1615–26. ©2011 AACR.
Data from PIK3R1 (p85α) Is Somatically Mutated at High Frequency in Primary Endometrial Cancer
Authors: Urick Mary E. , Rudd Meghan L. , Godwin Andrew K. , Sgroi Dennis , Merino Maria , Bell Daphne W.
Published: March 2024

Abstract
Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85α, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110α, and Western blotting of phospho-AKTSer473 (p-AKTSer473). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85α-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85α into U2OS cells reduced the level of p-AKTSer473 compared with the vector control. Five p85α mutants, p85αdelH450-E451, p85αdelK459, p85αdelY463-L466, p85αdelR574-T576, and the p85αN564D positive control, were shown to bind p110α and led to increased levels of p-AKTSer473. The p85αR348X and p85αK511VfsX2 mutants did not bind p110α and showed no appreciable change in p-AKTSer473 levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC. Cancer Res; 71(12); 4061–7. ©2011 AACR.
Data from RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma
Authors: Arai Akihito , Chano Tokuhiro , Futami Kazunobu , Furuichi Yasuhiro , Ikebuchi Kaichiro , Inui Takuma , Tameno Hitosuke , Ochi Yasuko , Shimada Taketoshi , Hisa Yasuo , Okabe Hidetoshi
Published: March 2024

Abstract
RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyper-recombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers. Cancer Res; 71(13); 4598–607. ©2011 AACR.
Data from Receptor Tyrosine Kinase Signaling Favors a Protumorigenic State in Breast Cancer Cells by Inhibiting the Adaptive Immune Response
Authors: Ursini-Siegel Josie , Cory Sean , Zuo Dongmei , Hardy William R. , Rexhepaj Elton , Lam Sonya , Schade Babette , Jirstrom Karin , Bjur Eva , Piccirillo Ciriaco A. , DeNardo David , Coussens Lisa M. , Brennan Donal J. , Gallagher William M. , Park Morag , Pawson Tony , Hallett Michael , Muller William J.
Published: March 2024

Abstract
Using transgenic mouse models of breast cancer that ablate Src homology and collagen A (ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4+ T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell–deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA-regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2+ and basal breast cancers. We reveal a novel role for tumor cell–derived ShcA in the establishment and maintenance of an immunosuppressive state. Cancer Res; 70(20); 7776–87. ©2010 AACR.
Data from Multiple Mutations and Bypass Mechanisms Can Contribute to Development of Acquired Resistance to MET Inhibitors
Authors: Qi Jie , McTigue Michele A. , Rogers Andrew , Lifshits Eugene , Christensen James G. , Jänne Pasi A. , Engelman Jeffrey A.
Published: March 2024

Abstract
Therapies targeting receptor tyrosine kinases have shown efficacy in molecularly defined subsets of cancers. Unfortunately, cancers invariably develop resistance, and overcoming or preventing resistance will ultimately be key to unleashing their full therapeutic potential. In this study, we examined how cancers become resistant to MET inhibitors, a class of drugs currently under clinical development. We utilized the highly sensitive gastric carcinoma cell line, SNU638, and two related MET inhibitors PHA-665752 and PF-2341066. To our surprise, we observed at least two mechanisms of resistance that arose simultaneously. Both resulted in maintenance of downstream PI3K (phosphoinositide 3-kinase)-AKT and MEK (MAP/ERK kinase)-ERK signaling in the presence of inhibitor. One mechanism, observed by modeling resistance both in vitro and in vivo, involved the acquisition of a mutation in the MET activation loop (Y1230). Structural analysis indicates that this mutation destabilizes the autoinhibitory conformation of MET and abrogates an important aromatic stacking interaction with the inhibitor. The other cause of resistance was activation of the epidermal growth factor receptor (EGFR) pathway due to increased expression of transforming growth factor α. Activation of EGFR bypassed the need for MET signaling to activate downstream signaling in these cells. This resistance could be overcome by combined EGFR and MET inhibition. Thus, therapeutic strategies that combine MET inhibitors capable of inhibiting Y1230 mutant MET in combination with anti-EGFR–based therapies may enhance clinical benefit for patients with MET-addicted cancers. Importantly, these results also underscore the notion that a single cancer can simultaneously develop resistance induced by several mechanisms and highlight the daunting challenges associated with preventing or overcoming resistance. Cancer Res; 71(3); 1081–91. ©2011 AACR.
Data from Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth
Authors: Drygin Denis , Lin Amy , Bliesath Josh , Ho Caroline B. , O'Brien Sean E. , Proffitt Chris , Omori Mayuko , Haddach Mustapha , Schwaebe Michael K. , Siddiqui-Jain Adam , Streiner Nicole , Quin Jaclyn E. , Sanij Elaine , Bywater Megan J. , Hannan Ross D. , Ryckman David , Anderes Kenna , Rice William G.
Published: March 2024

Abstract
Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell- and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I–driven transcription relative to Pol II–driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment. Cancer Res; 71(4); 1418–30. ©2010 AACR.
Data from MicroRNA-708 Induces Apoptosis and Suppresses Tumorigenicity in Renal Cancer Cells
Authors: Saini Sharanjot , Yamamura Soichiro , Majid Shahana , Shahryari Varahram , Hirata Hiroshi , Tanaka Yuichiro , Dahiya Rajvir
Published: March 2024

Abstract
Cancer pathogenesis is restricted by stresses that compromise cell division and survival. In this study, we identify miR-708, a little studied member of a set of microRNAs that have been implicated in stress control, as an important tumor suppressor in renal cell carcinoma (RCC). miR-708 expression was attenuated widely in human RCC specimens. Restoration of miR-708 expression in RCC cell lines decreased cell growth, clonability, invasion, and migration and elicited a dramatic increase in apoptosis. Moreover, intratumoral delivery of miR-708 was sufficient to trigger in vivo regression of established tumors in murine xenograft models of human RCC. Investigation of the targets of miR-708 identified the inhibitor of apoptosis protein survivin as important. siRNA-mediated knockdown of survivin partially phenocopied miR-708 overexpression suggesting that the proapoptotic role of miR-708 may be mediated primarily through survivin regulation. Additionally, we identified the E-cadherin regulators ZEB2 and BMI1 as likely miR-708 targets. Taken together, our findings define a major tumor suppressive role for miR-708, which may offer an attractive new target for prognostic and therapeutic intervention in RCC. Cancer Res; 71(19); 6208–19. ©2011 AACR.
Data from Podoplanin-Positive Fibroblasts Enhance Lung Adenocarcinoma Tumor Formation: Podoplanin in Fibroblast Functions for Tumor Progression
Authors: Hoshino Ayuko , Ishii Genichiro , Ito Takashi , Aoyagi Kazuhiko , Ohtaki Yoichi , Nagai Kanji , Sasaki Hiroki , Ochiai Atsushi
Published: March 2024

Abstract
During the metastatic process, cancer cells interact with vascular adventitial fibroblasts (VAF), which are the main components of the outermost connective tissue layer of blood vessels. This activity suggests the presence of a specific tumor microenvironment in the perivascular area. The s.c. coinjection of human lung adenocarcinoma cell lines (A549, PC-14, and CRL-5807) and human VAF (hVAF) resulted in a high rate of tumor formation, compared with the coinjection of these cell lines and human lung tissue-derived fibroblasts (hLF). A cDNA microarray analysis revealed a higher expression level of podoplanin in hVAFs than in hLFs (4.7-fold). Flow cytometry analysis also showed a higher expression level of podoplanin in hVAFs (43% ± 17.5%) than in hLFs (16% ± 10.3%). Sorted podoplanin-positive hVAFs displayed enhanced tumor formation, lymph node metastasis, and lung metastasis of A549 compared to sorted podoplanin-negative hVAFs. Knockdown of podoplanin in hVAFs decreased the augmenting effect of tumor formation and in vitro colony formation. The overexpression of podoplanin in hVAFs hastened the tumor formation of A549, compared with control hVAFs. Furthermore, the analysis of small-sized human lung adenocarcinoma (n = 112) revealed that patients with podoplanin-positive cancer-associated fibroblasts had a significantly higher rate of lymph node metastasis and a high risk of recurrence. These results indicate a promotive effect of hVAFs mediated by podoplanin on cancer progression and suggest that the perivascular environment may constitute a specific niche for tumor progression. Cancer Res; 71(14); 4769–79. ©2011 AACR.
Data from Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase Inhibitors
Authors: Lovly Christine M. , Heuckmann Johannes M. , de Stanchina Elisa , Chen Heidi , Thomas Roman K. , Liang Chris , Pao William
Published: March 2024

Abstract
Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B–ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies. Cancer Res; 71(14); 4920–31. ©2011 AACR.
Data from CXCR4 Signaling Regulates Metastasis of Chemoresistant Melanoma Cells by a Lymphatic Metastatic Niche
Authors: Kim Minah , Koh Young Jun , Kim Kyung Eun , Koh Bong Ihn , Nam Do-Hyun , Alitalo Kari , Kim Injune , Koh Gou Young
Published: March 2024

Abstract
Highly metastatic and chemotherapy-resistant properties of malignant melanomas stand as challenging barriers to successful treatment; yet, the mechanisms responsible for their aggressive characteristics are not fully defined. We show that a distinct population expressing CD133 (Prominin-1), which is highly enriched after administration of a chemotherapeutic drug, dacarbazine, has enhanced metastatic potential in vivo. CD133+ tumor cells are located close to tumor-associated lymphatic vessels in metastatic organs such as the regional lymph nodes and lung. Lymphatic endothelial cells promote the migratory activity of a CD133+ subset to target organs and regulation of lymphatic growth efficiently modulates the metastasis of CD133+ tumor cells. We found that lymphatic vessels in metastatic tissues stimulate chemokine receptor 4 (CXCR4)+/CD133+ cell metastasis to target organs by secretion of stromal cell–derived factor-1 (SDF-1). The CXCR4+/CD133+ cells exhibited higher metastatic activity compared with CXCR4−/CD133+ cells and, importantly, blockade of CXCR4 coupled with dacarbazine efficiently inhibited both tumor growth and metastasis; dacarbazine alone could not attenuate tumor metastasis. The current study demonstrates a previously unidentified role of the lymphatic microenvironment in facilitating metastasis of chemoresistant melanoma cells via a specific chemotactic axis, SDF-1/CXCR4. Our findings suggest that targeting the SDF-1/CXCR4 axis in addition to dacarbazine treatment could therapeutically block chemoresistant CD133+ cell metastasis toward a lymphatic metastatic niche. Cancer Res; 70(24); 10411–21. ©2010 AACR.
Data from Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer
Authors: Stevens Kristen N. , Vachon Celine M. , Lee Adam M. , Slager Susan , Lesnick Timothy , Olswold Curtis , Fasching Peter A. , Miron Penelope , Eccles Diana , Carpenter Jane E. , Godwin Andrew K. , Ambrosone Christine , Winqvist Robert , Brauch Hiltrud , Schmidt Marjanka K. , Cox Angela , Cross Simon S. , Sawyer Elinor , Hartmann Arndt , Beckmann Matthias W. , Schulz-Wendtland Rüdiger , Ekici Arif B. , Tapper William J. , Gerty Susan M. , Durcan Lorraine , Graham Nikki , Hein Rebecca , Nickels Stephan , Flesch-Janys Dieter , Heinz Judith , Sinn Hans-Peter , Konstantopoulou Irene , Fostira Florentia , Pectasides Dimitrios , Dimopoulos Athanasios M. , Fountzilas George , Clarke Christine L. , Balleine Rosemary , Olson Janet E. , Fredericksen Zachary , Diasio Robert B. , Pathak Harsh , Ross Eric , Weaver JoEllen , Rüdiger Thomas , Försti Asta , Dünnebier Thomas , Ademuyiwa Foluso , Kulkarni Swati , Pylkäs Katri , Jukkola-Vuorinen Arja , Ko Yon-Dschun , Van Limbergen Erik , Janssen Hilde , Peto Julian , Fletcher Olivia , Giles Graham G. , Baglietto Laura , Verhoef Senno , Tomlinson Ian , Kosma Veli-Matti , Beesley Jonathan , Greco Dario , Blomqvist Carl , Irwanto Astrid , Liu Jianjun , Blows Fiona M. , Dawson Sarah-Jane , Margolin Sara , Mannermaa Arto , Martin Nicholas G. , Montgomery Grant W. , Lambrechts Diether , dos Santos Silva Isabel , Severi Gianluca , Hamann Ute , Pharoah Paul , Easton Douglas F. , Chang-Claude Jenny , Yannoukakos Drakoulis , Nevanlinna Heli , Wang Xianshu , Couch Fergus J.
Published: March 2024

Abstract
Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer. Cancer Res; 71(19); 6240–9. ©2011 AACR.
Data from Positive Feedback Loop Between PI3K-Akt-mTORC1 Signaling and the Lipogenic Pathway Boosts Akt Signaling: Induction of the Lipogenic Pathway by a Melanoma Antigen
Authors: Yamauchi Yoshio , Furukawa Keiko , Hamamura Kazunori , Furukawa Koichi
Published: March 2024

Abstract
The lipogenic phenotype is a metabolic hallmark of cancer cells. Sterol regulatory element–binding proteins (SREBP) are key transcriptional factors to regulate biosynthesis of cholesterol and fatty acids. It has been poorly understood how the lipogenic phenotype in cancer cells is regulated and how it augments their malignant properties. Here we describe roles of the melanoma antigen ganglioside GD3 and phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR complex 1 (mTORC1) signaling in the regulation of SREBP activity, cholesterol biosynthesis, and the integrity of lipid rafts in human melanoma cells. GD3 expression induced the activation of both SREBP-1 and SREBP-2. Consequently, HMG-CoA reductase expression and cholesterol biosynthesis increased. The activation of the SREBP pathway was independent of the oncogenic BRAF mutation. On the other hand, it was regulated by PI3K-Akt-mTORC1 signaling in human melanoma cells. Disruption of the signaling pathway resulted in the reduction of cholesterol in lipid rafts. Inhibition of the SREBP pathway attenuated Akt activation in lipid rafts and suppressed the growth of human melanoma cells in vitro and in vivo. These results suggest that PI3K-Akt-mTORC1 signaling is important for the integrity of lipid rafts by regulating SREBP activation and subsequent cholesterogenesis. We thus propose a positive feedback circuit in which PI3K-Akt-mTORC1-SREBP signaling boosts Akt signaling in human melanoma cells expressing GD3. Cancer Res; 71(14); 4989–97. ©2011 AACR.
Data from Cancer Cell–Associated MT1-MMP Promotes Blood Vessel Invasion and Distant Metastasis in Triple-Negative Mammary Tumors
Authors: Perentes Jean Y. , Kirkpatrick Nathaniel D. , Nagano Satoshi , Smith Eve Y. , Shaver Christine M. , Sgroi Dennis , Garkavtsev Igor , Munn Lance L. , Jain Rakesh K. , Boucher Yves
Published: March 2024

Abstract
Functional roles for the cancer cell–associated membrane type I matrix metalloproteinase (MT1-MMP) during early steps of the metastatic cascade in primary tumors remain unresolved. In an effort to determine its significance, we determined the in vivo effects of RNAi-mediated downregulation in mammary cancer cells on the migration, blood and lymphatic vessel invasion (LVI), and lymph node and lung metastasis. We also correlated the expression of cancer cell MT1-MMP with blood vessel invasion (BVI) in 102 breast cancer biopsies. MT1-MMP downregulation in cancer cells decreased lung metastasis without affecting primary tumor growth. The inhibition of lung metastasis correlated with reduced cancer cell migration and BVI. Furthermore, cancer cell–expressed MT1-MMP upregulated the expression of MT1-MMP in vascular endothelial cells, but did not affect MT1-MMP expression in lymphatic endothelial cells, LVI, or lymph node metastasis. Of clinical importance, we observed that elevated MT1-MMP expression correlated with BVI in biopsies from triple-negative breast cancers (TNBC), which have a poor prognosis and high incidence of distant metastasis, relative to other breast cancer subtypes. Together, our findings established that MT1-MMP activity in breast tumors is essential for BVI, but not LVI, and that MT1-MMP should be further explored as a predictor and therapeutic target of hematogenous metastasis in TNBC patients. Cancer Res; 71(13); 4527–38. ©2011 AACR.
Data from Modulation of Cystatin A Expression in Human Airway Epithelium Related to Genotype, Smoking, COPD, and Lung Cancer
Authors: Butler Marcus W. , Fukui Tomoya , Salit Jacqueline , Shaykhiev Renat , Mezey Jason G. , Hackett Neil R. , Crystal Ronald G.
Published: March 2024

Abstract
The cathepsin inhibitor Cystatin A (CSTA) has antiapoptotic properties linked with neoplastic changes in squamous cell epithelium, where it has been proposed as a diagnostic and prognostic marker of lung cancer. Notably, cystatin A is upregulated in dysplastic epithelium, prompting us to hypothesize that it might be modulated in chronic obstructive pulmonary disease (COPD), a small airway epithelial (SAE) disorder that is a risk factor for non–small cell lung cancer (NSCLC) in a subset of smokers. Here we report that genetic variation, smoking, and COPD can all elevate levels of CSTA expression in lung small airway epithelia, with still further upregulation in squamous cell carcinoma (SCC), an NSCLC subtype. We examined SAE gene expression in 178 individuals, including healthy nonsmokers (n = 60), healthy smokers (n = 82), and COPD smokers (n = 36), with corresponding large airway epithelium (LAE) data included in a subset of subjects (n = 52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were found to associate with its expression in SAE. Levels were higher in COPD smokers than in healthy smokers, who, in turn, had higher levels than nonsmokers. CSTA gene expression in LAE was also smoking-responsive. Using publicly available NSCLC expression data we also found that CSTA was upregulated in SCC versus LAE and downregulated in adenocarcinoma versus smoke-exposed SAE. All phenotypes were associated with different proportional expression of CSTA to cathepsins. Our findings establish that genetic variability, smoking, and COPD all influence CSTA expression, as does SCC, supporting the concept that CSTA may make pivotal contributions to NSCLC pathogenesis in both early and late stages of disease development. Cancer Res; 71(7); 2572–81. ©2011 AACR.
Data from Pivotal Role of Innate and Adaptive Immunity in Anthracycline Chemotherapy of Established Tumors
Authors: Mattarollo Stephen R. , Loi Sherene , Duret Helene , Ma Yuting , Zitvogel Laurence , Smyth Mark J.
Published: March 2024

Abstract
We show, in a series of established experimental breast adenocarcinomas and fibrosarcomas induced by carcinogen de novo in mice, that the therapeutic efficacy of doxorubicin treatment is dependent on CD8 T cells and IFN-γ production. Doxorubicin treatment enhances tumor antigen–specific proliferation of CD8 T cells in tumor-draining lymph nodes and promotes tumor infiltration of activated, IFN-γ–producing CD8 T cells. Optimal doxorubicin treatment outcome also requires both interleukin (IL)-1β and IL-17 cytokines, as blockade of IL-1β/IL-1R or IL-17A/IL-17Rα signaling abrogated the therapeutic effect. IL-23p19 had no observed role. The presence of γδ T cells, but not Jα18+ natural killer T cells, at the time of doxorubicin treatment was also important. In tumor samples taken from breast cancer patients prior to treatment with anthracycline chemotherapy, a correlation between CD8α, CD8β, and IFN-γ gene expression levels and clinical response was observed, supporting their role in the therapeutic efficacy of anthracyclines in humans. Overall, these data strongly support the pivotal contribution of both innate and adaptive immunity in treatment outcomes of anthracycline chemotherapy. Cancer Res; 71(14); 4809–20. ©2011 AACR.
Data from Nox2 NADPH Oxidase Promotes Pathologic Cardiac Remodeling Associated with Doxorubicin Chemotherapy
Authors: Zhao Youyou , McLaughlin Declan , Robinson Emma , Harvey Adam P. , Hookham Michelle B. , Shah Ajay M. , McDermott Barbara J. , Grieve David J.
Published: March 2024

Abstract
Doxorubicin is a highly effective cancer treatment whose use is severely limited by dose-dependent cardiotoxicity. It is well established that doxorubicin increases reactive oxygen species (ROS) production. In this study, we investigated contributions to doxorubicin cardiotoxicity from Nox2 NADPH oxidase, an important ROS source in cardiac cells, which is known to modulate several key processes underlying the myocardial response to injury. Nox2-deficient mice (Nox2−/−) and wild-type (WT) controls were injected with doxorubicin (12 mg/kg) or vehicle and studied 8 weeks later. Echocardiography indicated that doxorubicin-induced contractile dysfunction was attenuated in Nox2−/− versus WT mice (fractional shortening: 29.5 ± 1.4 versus 25.7 ± 1.0%; P < 0.05). Similarly, in vivo pressure-volume analysis revealed that systolic and diastolic function was preserved in doxorubicin-treated Nox2−/− versus WT mice (ejection fraction: 52.6 ± 2.5 versus 28.5 ± 2.3%, LVdP/dtmin: −8,379 ± 416 versus −5,198 ± 527 mmHg s−1; end-diastolic pressure-volume relation: 0.051 ± 0.009 versus 0.114 ± 0.012; P < 0.001). Furthermore, in response to doxorubicin, Nox2−/− mice exhibited less myocardial atrophy, cardiomyocyte apoptosis, and interstitial fibrosis, together with reduced increases in profibrotic gene expression (procollagen IIIαI, transforming growth factor-β3, and connective tissue growth factor) and matrix metalloproteinase-9 activity, versus WT controls. These alterations were associated with beneficial changes in NADPH oxidase activity, oxidative/nitrosative stress, and inflammatory cell infiltration. We found that adverse effects of doxorubicin were attenuated by acute or chronic treatment with the AT1 receptor antagonist losartan, which is commonly used to reduce blood pressure. Our findings suggest that ROS specifically derived from Nox2 NADPH oxidase make a substantial contribution to several key processes underlying development of cardiac contractile dysfunction and remodeling associated with doxorubicin chemotherapy. Cancer Res; 70(22); 9287–97. ©2010 AACR.
Data from Autophagic Survival in Resistance to Histone Deacetylase Inhibitors: Novel Strategies to Treat Malignant Peripheral Nerve Sheath Tumors
Authors: Lopez Gonzalo , Torres Keila , Liu Juehui , Hernandez Belinda , Young Eric , Belousov Roman , Bolshakov Svetlana , Lazar Alexander J. , Slopis John M. , McCutcheon Ian E. , McConkey David , Lev Dina
Published: March 2024

Abstract
Histone deacetylase inhibitors (HDACi) show promise as cancer therapeutics; however, the full scope of their utility remains unknown. Here we report findings that strongly rationalize clinical evaluation of HDACis in malignant peripheral nerve sheath tumors (MPNST), a class of highly aggressive, therapeutically resistant, and commonly fatal malignancies that occur sporadically or in patients with the inherited neurofibromatosis type-1 (NF1) syndrome. We evaluated the effects of the chemical HDACis PCI-24781, suberoylanilide hydroxamic acid, and MS-275 on a panel of human NF1-associated and sporadic MPNSTs in vitro and in vivo. A subset of MPNSTs was found to be highly sensitive to HDACis, especially to PCI-24781. All cell lines in this group were NF1-associated. Significant proapoptotic effects were noted in vitro and in vivo and were independent of p53 mutational status. In contrast, as a group the sporadic–MPNST cells were markedly resistant to HDACi treatment. HDACis were found to induce productive autophagy in MPNST cells. Genetic and/or pharmacologic autophagy blockade resulted in significant HDACi-induced apoptosis in cells defined as resistant or sensitive, leading to abrogated growth of primary tumors and lung metastases in tumor xenograft assays. Among autophagy-associated genes expressed in response to HDACi, the immunity-related GTPase family, M was validated as a critical target in mediating HDACi-induced autophagy and enhanced apoptosis. Taken together, our findings strongly support the evaluation of HDACi currently in clinical trials as an important new therapeutic strategy to treat MPNST, including in combination with autophagy blocking combination regimens in particular for patients with sporadic MPNST. Cancer Res; 71(1); 185–96. ©2010 AACR.
Data from p53 Dysfunction by Xeroderma Pigmentosum Group C Defects Enhance Lung Adenocarcinoma Metastasis via Increased Mmp1 Expression
Authors: Wu Yi-Hui , Wu Tzu-Chin , Liao Jiunn-Wang , Yeh Kun-Tu , Chen Chih-Yi , Lee Huei
Published: March 2024

Abstract
Xeroderma pigmentosum group C (XPC) interacts with hHR23B to recognize DNA damage in global genomic repair. We previously showed that XPC is predominantly affected by its hypermethylation and is associated with an increased occurrence of p53 mutation in lung cancer. Tumors with low XPC mRNA levels had a poorer prognosis than those with high XPC mRNA levels, suggesting that XPC defects may enhance tumor metastasis. However, the underlying mechanism is unclear. Here, we show that p53 transcriptional activity is modulated by XPC, whereby XPC stabilizes hHR23B to form an hHR23B–p53 complex that prevents p53 degradation. In addition, in lung cancer cells and xenograft tumors in nude mice, overexpression of XPC suppresses cell/tumor metastatic ability via repression of matrix metalloproteinase-1 (MMP1) transcription by p53. Among tumors from lung cancer patients, those with low XPC mRNA also tended to have low expression of MMP1 mRNA compared with those with high XPC mRNA. Patients with low XPC mRNA levels also more commonly had tumors with late-stage, distant metastasis (M1), nodal metastasis, and T value (P < 0.001 for tumor stage, distant metastasis, and nodal metastasis; P = 0.006 for t value). In conclusion, p53 dysfunction caused by XPC defects in lung cancers may enhance tumor metastasis via increased MMP1 expression. Cancer Res; 70(24); 10422–32. ©2010 AACR.
Data from Characterization of Chemokines and Adhesion Molecules Associated with T cell Presence in Tertiary Lymphoid Structures in Human Lung Cancer
Authors: de Chaisemartin Luc , Goc Jérémy , Damotte Diane , Validire Pierre , Magdeleinat Pierre , Alifano Marco , Cremer Isabelle , Fridman Wolf-Herman , Sautès-Fridman Catherine , Dieu-Nosjean Marie-Caroline
Published: March 2024

Abstract
De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they represent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found that most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins (alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. Intratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies. Cancer Res; 71(20); 6391–9. ©2011 AACR.
Data from Two Novel Determinants of Etoposide Resistance in Small Cell Lung Cancer
Authors: Lawson Malcolm H. , Cummings Natalie M. , Rassl Doris M. , Russell Roslin , Brenton James D. , Rintoul Robert C. , Murphy Gillian
Published: March 2024

Abstract
Patient survival in small cell lung cancer (SCLC) is limited by acquired chemoresistance. Here we report the use of a biologically relevant model to identify novel candidate genes mediating in vivo acquired resistance to etoposide. Candidate genes derived from a cDNA microarray analysis were cloned and transiently overexpressed to evaluate their potential functional roles. We identified two promising genes in the DNA repair enzyme DNA polymerase β and in the neuroendocrine transcription factor NKX2.2. Specific inhibition of DNA polymerase β reduced the numbers of cells surviving treatment with etoposide and increased the amount of DNA damage in cells. Conversely, stable overexpression of NKX2.2 increased cell survival in response to etoposide in SCLC cell lines. Consistent with these findings, we found that an absence of nuclear staining for NKX2.2 in SCLC primary tumors was an independent predictor of improved outcomes in chemotherapy-treated patients. Taken together, our findings justify future prospective studies to confirm the roles of these molecules in mediating chemotherapy resistance in SCLC. Cancer Res; 71(14); 4877–87. ©2011 AACR.
Data from Retinoic Acid Enhances TRAIL-Induced Apoptosis in Cancer Cells by Upregulating TRAIL Receptor 1 Expression
Authors: Dhandapani Latha , Yue Ping , Ramalingam Suresh S. , Khuri Fadlo R. , Sun Shi-Yong
Published: March 2024

Abstract
Many human cancer cells are sensitive to killing by the proapoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL), which is under study for cancer treatment in clinical trials. The TRAIL receptor (TRAIL-R1; also known as death receptor 4) is a transmembrane receptor that mediates TRAIL-induced apoptosis in cancer cells. In this study, we show that retinoids sensitize cancer cells to TRAIL-induced apoptosis by upregulating expression of TRAIL-R1. All-trans retinoic acid (ATRA) upregulated TRAIL-R1 expression in human cancer cells at the transcriptional level. The ability of ATRA to activate TRAIL-R1 expression was inhibited by retinoic acid receptor (RAR) antagonists or siRNAs, but augmented by several RAR agonists. In analyzing how ATRA induces RAR-dependent transcriptional upregulation of TRAIL-R1, we identified 2 putative retinoic acid response elements termed Pal-17 (a palindrome separated by 17 bases) and DR-11 (a direct repeat separated by 11 bases) in the 5′-flanking region of TRAIL-R1 gene. Deletion of DR-11, but not Pal-17, abrogated the ability of ATRA to stimulate TRAIL-R1 promoter activity. Consistent with this observation, RAR binding to DR-11, but not to Pal-17, was detected by chromatin immunoprecipitation assay in ATRA-treated cells, arguing that DR-11 was responsible for ATRA-mediated activation of the TRAIL-R1 gene. ATRA augmented TRAIL-induced apoptosis of cancer cells, and this activity was attenuated by a blockade to upregulation of TRAIL-R1 expression. Taken together, our findings establish that ATRA accentuates TRAIL-induced apoptosis, reveal a novel mechanism by which retinoids modulate apoptosis, and suggest a novel strategy to augment the anti-cancer activity of TRAIL. Cancer Res; 71(15); 5245–54. ©2011 AACR.
Data from Protein Arginine Methyltransferase 5 Accelerates Tumor Growth by Arginine Methylation of the Tumor Suppressor Programmed Cell Death 4
Authors: Powers Matthew A. , Fay Marta M. , Factor Rachel E. , Welm Alana L. , Ullman Katharine S.
Published: March 2024

Abstract
Programmed cell death 4 (PDCD4) has been described as a tumor suppressor, with high expression correlating with better outcomes in a number of cancer types. Yet a substantial number of cancer patients with high PDCD4 in tumors have poor survival, suggesting that oncogenic pathways may inhibit or change PDCD4 function. Here, we explore the significance of PDCD4 in breast cancer and identify protein arginine methyltransferase 5 (PRMT5) as a cofactor that radically alters PDCD4 function. Specifically, we find that coexpression of PDCD4 and PRMT5 in an orthotopic model of breast cancer causes accelerated tumor growth and that this growth phenotype is dependent on both the catalytic activity of PRMT5 and a site of methylation within the N-terminal region of PDCD4. In agreement with the xenograft model, elevated PDCD4 expression was found to correlate with worse outcome within the cohort of breast cancer patients whose tumors contain higher levels of PRMT5. These results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy. Cancer Res; 71(16); 5579–87. ©2011 AACR.