bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Data from Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers
Authors: Lin Eva , Li Li , Guan Yinghui , Soriano Robert , Rivers Celina Sanchez , Mohan Sankar , Pandita Ajay , Tang Jerry , Modrusan Zora
Published: April 2023

Supplementary Data from Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers
Supplementary Data from Focused PCR Screen Reveals p53 Dependence of Nitric Oxide-Induced Apoptosis and Up-Regulation of Maspin and Plasminogen Activator Inhibitor-1 in Tumor Cells
Authors: Lim Shuhui , Hung Amos C. , Porter Alan G.
Published: April 2023

Supplementary Data from Focused PCR Screen Reveals p53 Dependence of Nitric Oxide-Induced Apoptosis and Up-Regulation of Maspin and Plasminogen Activator Inhibitor-1 in Tumor Cells
Supplementary Tables 1-2, Figures 1-4 from Constitutive Aberrant Endogenous Interleukin-1 Facilitates Inflammation and Growth in Human Melanoma
Authors: Qin Yong , Ekmekcioglu Suhendan , Liu Ping , Duncan Lyn M. , Lizée Gregory , Poindexter Nancy , Grimm Elizabeth A.
Published: April 2023

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Supplementary Data from Upregulation of MMP-2 by HMGA1 Promotes Transformation in Undifferentiated, Large-Cell Lung Cancer
Authors: Hillion Joelle , Wood Lisa J. , Mukherjee Mita , Bhattacharya Raka , Di Cello Francescopaolo , Kowalski Jeanne , Elbahloul Ossama , Segal Jodi , Poirier John , Rudin Charles M. , Dhara Surajit , Belton Amy , Joseph Biju , Zucker Stanley , Resar Linda M.S.
Published: April 2023

Supplementary Data from Upregulation of MMP-2 by HMGA1 Promotes Transformation in Undifferentiated, Large-Cell Lung Cancer
Supplementary Data from Thiacremonone Augments Chemotherapeutic Agent–Induced Growth Inhibition in Human Colon Cancer Cells through Inactivation of Nuclear Factor-κB
Authors: Ban Jung Ok , Lee Hee Soon , Jeong Heon-Sang , Song Sugkil , Hwang Bang Yeon , Moon Dong Cheul , Yoon Do Young , Han Sang Bae , Hong Jin Tae
Published: April 2023

Supplementary Data from Thiacremonone Augments Chemotherapeutic Agent–Induced Growth Inhibition in Human Colon Cancer Cells through Inactivation of Nuclear Factor-κB
Supplementary Figure 2 from Forced Dimerization Increases the Activity of ΔEGFR/EGFRvIII and Enhances Its Oncogenicity
Authors: Hwang Yeohyeon , Chumbalkar Vaibhav , Latha Khatri , Bogler Oliver
Published: April 2023

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Supplementary Figures S1-S2 from miR-15 and miR-16 Are Direct Transcriptional Targets of E2F1 that Limit E2F-Induced Proliferation by Targeting Cyclin E
Authors: Ofir Matan , Hacohen Dalia , Ginsberg Doron
Published: April 2023

Supplementary Figures S1-S2.
Supplementary Figure S1 from Nitric Oxide Inhibits the Proliferation and Invasion of Pancreatic Cancer Cells through Degradation of Insulin Receptor Substrate-1 Protein
Authors: Sugita Hiroki , Kaneki Masao , Furuhashi Satoshi , Hirota Masahiko , Takamori Hiroshi , Baba Hideo
Published: April 2023

Supplementary Figure S1.
Supplementary Table 2 from Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ–Mediated Tumor Elimination
Authors: Piya Sujan , Moon Ae Ran , Song Peter I. , Hiscott John , Lin Rongtuan , Seol Dai-Wu , Kim Tae-Hyoung
Published: April 2023

PDF file - 1.8MB
Supplementary Figure 4 from Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ–Mediated Tumor Elimination
Authors: Piya Sujan , Moon Ae Ran , Song Peter I. , Hiscott John , Lin Rongtuan , Seol Dai-Wu , Kim Tae-Hyoung
Published: April 2023

PDF file - 630K
Supplementary Data from Identification of CD44 as a Surface Biomarker for Drug Resistance by Surface Proteome Signature Technology
Authors: Cain Jason W. , Hauptschein Robert S. , Stewart Jean K. , Bagci Tugba , Sahagian Gary G. , Jay Daniel G.
Published: April 2023

Supplementary Figures S1-S3; Supplementary Methods.
Supplementary Figure 2 from Upregulation of ABCG2 by Romidepsin via the Aryl Hydrocarbon Receptor Pathway
Authors: To Kenneth K.W. , Robey Robert , Zhan Zhirong , Bangiolo Lois , Bates Susan E.
Published: April 2023

S2. ABCG2 promoter luciferase reporter assay was repeated in S1 cells stably transfected with a silencing vector for AhR (pU6-AhR).
Supplementary Figure 1 from Upregulation of ABCG2 by Romidepsin via the Aryl Hydrocarbon Receptor Pathway
Authors: To Kenneth K.W. , Robey Robert , Zhan Zhirong , Bangiolo Lois , Bates Susan E.
Published: April 2023

S1. Real-time PCR analysis showing the cell-line specific upregulation of ABCG2 by romidepsin or B(a)P.
Supplementary Data from Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex
Authors: Brooks Alan D. , Jacobsen Kristen M. , Li Wenqing , Shanker Anil , Sayers Thomas J.
Published: April 2023

Supplementary Data from Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex
Supplementary Figure S1 from PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-κB Activation
Authors: Tanaka Hiroshi , Hoshikawa Yutaka , Oh-hara Tomoko , Koike Sumie , Naito Mikihiko , Noda Tetsuo , Arai Hiroyuki , Tsuruo Takashi , Fujita Naoya
Published: April 2023

Supplementary Figure S1 from PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-κB Activation
Supplementary Figures 1-4, Table 1 from Loss of Trop2 Promotes Carcinogenesis and Features of Epithelial to Mesenchymal Transition in Squamous Cell Carcinoma
Authors: Wang Jianbo , Zhang Kaihua , Grabowska Dorota , Li Aimin , Dong Yiyu , Day Ryan , Humphrey Peter , Lewis James , Kladney Raleigh D. , Arbeit Jeffrey M. , Weber Jason D. , Chung Christine H. , Michel Loren S.
Published: April 2023

PDF file - 264K
Supplementary Figure S1 from Metformin Induces Both Caspase-Dependent and Poly(ADP-ribose) Polymerase-Dependent Cell Death in Breast Cancer Cells
Authors: Zhuang Yongxian , Miskimins W. Keith
Published: April 2023

Supplementary Figure S1 from Metformin Induces Both Caspase-Dependent and Poly(ADP-ribose) Polymerase-Dependent Cell Death in Breast Cancer Cells
Supplementary Methods from Lrig1 Is an Estrogen-Regulated Growth Suppressor and Correlates with Longer Relapse-Free Survival in ERα-Positive Breast Cancer
Authors: Krig Sheryl R. , Frietze Seth , Simion Catalina , Miller Jamie K. , Fry Will H.D. , Rafidi Hanine , Kotelawala Lakmal , Qi Lihong , Griffith Obi L. , Gray Joe W. , Carraway Kermit L. , Sweeney Colleen
Published: April 2023

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Supplementary Figure 7 from Lrig1 Is an Estrogen-Regulated Growth Suppressor and Correlates with Longer Relapse-Free Survival in ERα-Positive Breast Cancer
Authors: Krig Sheryl R. , Frietze Seth , Simion Catalina , Miller Jamie K. , Fry Will H.D. , Rafidi Hanine , Kotelawala Lakmal , Qi Lihong , Griffith Obi L. , Gray Joe W. , Carraway Kermit L. , Sweeney Colleen
Published: April 2023

PDF file - 1.35MB
Supplementary Figure 2 from Resveratrol Inhibits Proliferation and Survival of Epstein Barr Virus–Infected Burkitt's Lymphoma Cells Depending on Viral Latency Program
Authors: De Leo Alessandra , Arena Giuseppe , Stecca Claudia , Raciti Marisa , Mattia Elena
Published: April 2023

PDF File - (1112K) - Supershift assay . The cell extracts from control cells and cells treated for three hours with RV, were incubated with anti-p65 or anti-p50 antibodies and analyzed by EMSA. Lane 1, without cell extract; Lane 2 and 6, kB probe alone; Lane 3 and 7, with p65 antibody; Lane 4 and 8 with p50 antibody; Lane 5, unlabeled probe.
Supplementary Data from Distinct Roles for Histone Methyltransferases G9a and GLP in Cancer Germ-Line Antigen Gene Regulation in Human Cancer Cells and Murine Embryonic Stem Cells
Authors: Link Petra A. , Gangisetty Omkaram , James Smitha R. , Woloszynska-Read Anna , Tachibana Makoto , Shinkai Yoichi , Karpf Adam R.
Published: April 2023

Supplementary Data from Distinct Roles for Histone Methyltransferases G9a and GLP in Cancer Germ-Line Antigen Gene Regulation in Human Cancer Cells and Murine Embryonic Stem Cells
Supplementary Figure 1 from The ARF Tumor Suppressor Inhibits Tumor Cell Colonization Independent of p53 in a Novel Mouse Model of Pancreatic Ductal Adenocarcinoma Metastasis
Authors: Muniz Viviane Palhares , Barnes J. Matthew , Paliwal Seema , Zhang Xuefeng , Tang Xiaoyun , Chen Songhai , Zamba Kokou D. , Cullen Joseph J. , Meyerholz David K. , Meyers Shari , Davis J. Nathan , Grossman Steven R. , Henry Michael D. , Quelle Dawn E.
Published: April 2023

Supplementary Figure 1 from The ARF Tumor Suppressor Inhibits Tumor Cell Colonization Independent of p53 in a Novel Mouse Model of Pancreatic Ductal Adenocarcinoma Metastasis
Supplementary Table S2 from Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines
Authors: Coldren Christopher D. , Helfrich Barbara A. , Witta Samir E. , Sugita Michio , Lapadat Razvan , Zeng Chan , Barón Anna , Franklin Wilbur A. , Hirsch Fred R. , Geraci Mark W. , Bunn Paul A.
Published: April 2023

Supplementary Table S2 from Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines
Supplementary Data from Mutant p53 (G199V) Gains Antiapoptotic Function through Signal Transducer and Activator of Transcription 3 in Anaplastic Thyroid Cancer Cells
Authors: Kim Tae-Hyun , Lee Sang Yull , Rho Jee Hyun , Jeong Na Young , Soung Young Hwa , Jo Wol Soon , Kang Do-Young , Kim Sung-Heun , Yoo Young Hyun
Published: April 2023

Supplementary Data from Mutant p53 (G199V) Gains Antiapoptotic Function through Signal Transducer and Activator of Transcription 3 in Anaplastic Thyroid Cancer Cells
Supplementary Figures S1-S4 from Constitutive Suppressor of Cytokine Signaling 3 Expression Confers a Growth Advantage to a Human Melanoma Cell Line
Authors: Komyod Waraporn , Böhm Markus , Metze Dieter , Heinrich Peter C. , Behrmann Iris
Published: April 2023

Supplementary Figures S1-S4 from Constitutive Suppressor of Cytokine Signaling 3 Expression Confers a Growth Advantage to a Human Melanoma Cell Line
Supplementary Table S2 from Microarray Analysis of Bleomycin-Exposed Lymphoblastoid Cells for Identifying Cancer Susceptibility Genes
Authors: Cloos Jacqueline , de Boer Wim P.H. , Snel Mireille H.J. , van den IJssel Paul , Ylstra Bauke , Leemans C. René , Brakenhoff Ruud H. , Braakhuis Boudewijn J.M.
Published: April 2023

Gene list: sensitive vs insensitive comparison
Supplementary Table S6 from Ataxia Telangiectasia-Mutated–Dependent DNA Damage Checkpoint Functions Regulate Gene Expression in Human Fibroblasts
Authors: Zhou Tong , Chou Jeff , Zhou Yingchun , Simpson Dennis A. , Cao Feng , Bushel Pierre R. , Paules Richard S. , Kaufmann William K.
Published: April 2023

Supplementary Table S6 from Ataxia Telangiectasia-Mutated–Dependent DNA Damage Checkpoint Functions Regulate Gene Expression in Human Fibroblasts
Supplementary Table S1 from Ataxia Telangiectasia-Mutated–Dependent DNA Damage Checkpoint Functions Regulate Gene Expression in Human Fibroblasts
Authors: Zhou Tong , Chou Jeff , Zhou Yingchun , Simpson Dennis A. , Cao Feng , Bushel Pierre R. , Paules Richard S. , Kaufmann William K.
Published: April 2023

Supplementary Table S1 from Ataxia Telangiectasia-Mutated–Dependent DNA Damage Checkpoint Functions Regulate Gene Expression in Human Fibroblasts
Supplementary Data 3 from Genomic Analysis of a Spontaneous Model of Breast Cancer Metastasis to Bone Reveals a Role for the Extracellular Matrix1
Authors: Eckhardt Bedrich L. , Parker Belinda S. , van Laar Ryan K. , Restall Christina M. , Natoli Anthony L. , Tavaria Michael D. , Stanley Kym L. , Sloan Erica K. , Moseley Jane M. , Anderson Robin L.
Published: April 2023

Genes altered between highly and weakly metastatic tumors
Supplementary Data 2 from Genomic Analysis of a Spontaneous Model of Breast Cancer Metastasis to Bone Reveals a Role for the Extracellular Matrix1
Authors: Eckhardt Bedrich L. , Parker Belinda S. , van Laar Ryan K. , Restall Christina M. , Natoli Anthony L. , Tavaria Michael D. , Stanley Kym L. , Sloan Erica K. , Moseley Jane M. , Anderson Robin L.
Published: April 2023

Assays that do not distinguish metastatic phenotype
Supplementary Table S2 from Integrative Genomic Analysis of Small-Cell Lung Carcinoma Reveals Correlates of Sensitivity to Bcl-2 Antagonists and Uncovers Novel Chromosomal Gains
Authors: Olejniczak Edward T. , Van Sant Charles , Anderson Mark G. , Wang Gang , Tahir Stephen K. , Sauter Guido , Lesniewski Rick , Semizarov Dimitri
Published: April 2023

Supplementary Table S2 from Integrative Genomic Analysis of Small-Cell Lung Carcinoma Reveals Correlates of Sensitivity to Bcl-2 Antagonists and Uncovers Novel Chromosomal Gains
Supplementary Figure S2 from A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents
Authors: McNeill Daniel R. , Wilson David M.
Published: April 2023

Supplementary Figure S2 from A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents
Supplementary Figure S1 from A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents
Authors: McNeill Daniel R. , Wilson David M.
Published: April 2023

Supplementary Figure S1 from A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents
Supplementary Data from PU.1 Activation Relieves GATA-1–Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation
Authors: Burda Pavel , Curik Nikola , Kokavec Juraj , Basova Petra , Mikulenkova Dana , Skoultchi Arthur I. , Zavadil Jiri , Stopka Tomas
Published: April 2023

Supplementary Data from PU.1 Activation Relieves GATA-1–Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation
Supplementary Table S6 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Authors: Xu Lei , Shen Steven S. , Hoshida Yujin , Subramanian Aravind , Ross Ken , Brunet Jean-Philippe , Wagner Stephan N. , Ramaswamy Sridhar , Mesirov Jill P. , Hynes Richard O.
Published: April 2023

Supplementary Table S6 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Supplementary Table S4 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Authors: Xu Lei , Shen Steven S. , Hoshida Yujin , Subramanian Aravind , Ross Ken , Brunet Jean-Philippe , Wagner Stephan N. , Ramaswamy Sridhar , Mesirov Jill P. , Hynes Richard O.
Published: April 2023

Supplementary Table S4 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Supplementary Table S3 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Authors: Xu Lei , Shen Steven S. , Hoshida Yujin , Subramanian Aravind , Ross Ken , Brunet Jean-Philippe , Wagner Stephan N. , Ramaswamy Sridhar , Mesirov Jill P. , Hynes Richard O.
Published: April 2023

Supplementary Table S3 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Supplementary Table S1 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Authors: Xu Lei , Shen Steven S. , Hoshida Yujin , Subramanian Aravind , Ross Ken , Brunet Jean-Philippe , Wagner Stephan N. , Ramaswamy Sridhar , Mesirov Jill P. , Hynes Richard O.
Published: April 2023

Supplementary Table S1 from Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Supplementary Table S1 from Targeting Bladder Tumor Cells In vivo and in the Urine with a Peptide Identified by Phage Display
Authors: Lee Seung-Min , Lee Eun-Ju , Hong Hai-Yan , Kwon Mi-Kyung , Kwon Tae-Hwan , Choi Je-Yong , Park Rang-Woon , Kwon Tae-Gyun , Yoo Eun-Sang , Yoon Gil-Suk , Kim In-San , Ruoslahti Erkki , Lee Byung-Heon
Published: April 2023

Supplementary Table S1 from Targeting Bladder Tumor Cells In vivo and in the Urine with a Peptide Identified by Phage Display
Supplementary Figures S1-S6 from Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation
Authors: Kadenhe-Chiweshe Angela , Papa Joey , McCrudden Kimberly W. , Frischer Jason , Bae Jae-O , Huang Jianzhong , Fisher Jason , Lefkowitch Jay H. , Feirt Nikki , Rudge John , Holash Jocelyn , Yancopoulos George D. , Kandel Jessica J. , Yamashiro Darrell J.
Published: April 2023

Supplementary Figures S1-S6 from Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation
Supplementary Data from Notch Signal Activates Hypoxia Pathway through HES1-Dependent SRC/Signal Transducers and Activators of Transcription 3 Pathway
Authors: Lee Jae Ho , Suk Jinkyu , Park Jinhwi , Kim Seung Beom , Kwak Sang Su , Kim Jin Woo , Lee Chan Hee , Byun Boohyeong , Ahn Jeong Keun , Joe Cheol O.
Published: April 2023

Supplementary Data from Notch Signal Activates Hypoxia Pathway through HES1-Dependent SRC/Signal Transducers and Activators of Transcription 3 Pathway
Supplementary Data from Effect of an Epidermal Growth Factor Receptor Inhibitor in Mouse Models of Lung Cancer
Authors: Yan Ying , Lu Yan , Wang Min , Vikis Haris , Yao Ruisheng , Wang Yian , Lubet Ronald A. , You Ming
Published: April 2023

Supplementary Data from Effect of an Epidermal Growth Factor Receptor Inhibitor in Mouse Models of Lung Cancer
Supplementary Table S1 from Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes
Authors: Ji Youngmi , Prasad Nijaguna B. , Novotny Elizabeth A. , Kaur Sukhbir , Elkahloun Abdel , Chen Yidong , Zhang Rui-Zhu , Chu Mon-Li , Agarwal Sunita K. , Marx Stephen J. , Collins Francis S. , Chandrasekharappa Settara C.
Published: April 2023

Supplementary Table S1 from Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes
Supplementary Data 1 from NR0B1 Is Required for the Oncogenic Phenotype Mediated by EWS/FLI in Ewing's Sarcoma
Authors: Kinsey Michelle , Smith Richard , Lessnick Stephen L.
Published: April 2023

RES file
Supplementary Data from Genomic Changes and Gene Expression Profiles Reveal That Established Glioma Cell Lines Are Poorly Representative of Primary Human Gliomas
Authors: Li Aiguo , Walling Jennifer , Kotliarov Yuri , Center Angela , Steed Mary Ellen , Ahn Susie J. , Rosenblum Mark , Mikkelsen Tom , Zenklusen Jean Claude , Fine Howard A.
Published: April 2023

Supplementary Data from Genomic Changes and Gene Expression Profiles Reveal That Established Glioma Cell Lines Are Poorly Representative of Primary Human Gliomas
Supplementary Table 3 from Molecular Characterization of the Transition to Malignancy in a Genetically Engineered Mouse-Based Model of Ductal Carcinoma In situ1
Authors: Namba Ruria , Maglione Jeannie E. , Young Lawrence J.T. , Borowsky Alexander D. , Cardiff Robert D. , MacLeod Carol L. , Gregg Jeffrey P.
Published: April 2023

Supplementary Table 3 from Molecular Characterization of the Transition to Malignancy in a Genetically Engineered Mouse-Based Model of Ductal Carcinoma In situ1
Supplementary Data from Transcriptome Profile of Human Colorectal Adenomas
Authors: Sabates-Bellver Jacob , Van der Flier Laurens G. , de Palo Mariagrazia , Cattaneo Elisa , Maake Caroline , Rehrauer Hubert , Laczko Endre , Kurowski Michal A. , Bujnicki Janusz M. , Menigatti Mirco , Luz Judith , Ranalli Teresa V. , Gomes Vito , Pastorelli Alfredo , Faggiani Roberto , Anti Marcello , Jiricny Josef , Clevers Hans , Marra Giancarlo
Published: April 2023

Supplementary Data from Transcriptome Profile of Human Colorectal Adenomas
Supplementary Figures S1-S2 from Visible Light Modulates the Expression of Cancer-Retina Antigens
Authors: Bazhin Alexandr V. , Schadendorf Dirk , Owen Robert W. , Zernii Evgeni Yu , Philippov Pavel P. , Eichmüller Stefan B.
Published: April 2023

Supplementary Figures S1-S2 from Visible Light Modulates the Expression of Cancer-Retina Antigens
Data from Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors
Authors: Fenton Sarah E. , Zannikou Markella , Ilut Liliana , Fischietti Mariafausta , Ji Chunni , Oku Chidera V. , Horvath Curt M. , Le Poole I. Caroline , Bosenberg Marcus , Bartom Elizabeth T. , Kocherginsky Masha , Platanias Leonidas C. , Saleiro Diana
Published: April 2023

Abstract
Immune checkpoint inhibitors (ICI) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. IFNγ signaling and the expression of IFNγ-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNγ-inducible immunostimulatory genes are required for response to ICIs, chronic IFNγ signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of Unc-51 like kinase 1 (ULK1) correlate with poor survival in patients with melanoma and overexpression of ULK1 in melanoma cells enhances IFNγ-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacologic inhibition of ULK1 reduces expression of IFNγ-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the programmed death-ligand 1 promoter region. In addition, pharmacologic inhibition of ULK1 in combination with anti-programmed cell death protein 1 therapy further reduces melanoma tumor growth in vivo. Our data suggest that targeting ULK1 represses IFNγ-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of patients with melanoma to improve response rates and patient outcomes.
Implications:
This study identifies ULK1, activated downstream of IFNγ signaling, as a druggable target to overcome resistance mechanisms to ICI therapy in metastatic melanoma.
Data from Therapeutic Effect of Quinacrine, an Antiprotozoan Drug, by Selective Suppression of p-CHK1/2 in p53-Negative Malignant Cancers
Authors: Park Soyoung , Oh Ah-Young , Cho Jung-Hyun , Yoon Min-Ho , Woo Tae-Gyun , Kang So-mi , Lee Ho-Young , Jung Youn-Jin , Park Bum-Joon
Published: April 2023

Abstract
Quinacrine (QNC), antiprotozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest antitumor effects of QNC through suppression of NF-κB and activation of p53. This study demonstrates the anticancer effect of QNC via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions. Inhibition of p53 by PFT-α or siRNA promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G2–M phase. QNC increases the binding between p-Chk1/2 and β-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed antitumor effects in a Villin-Cre;p53+/LSL-R172H intestinal cancer mouse model system as well as HCT116 p53−/− xenografts.

Implications: QNC has been used for the past over 70 years without obvious side effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies. Mol Cancer Res; 16(6); 935–46. ©2018 AACR.
Data from Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress
Authors: Laurent Victor , Toulet Aurélie , Attané Camille , Milhas Delphine , Dauvillier Stéphanie , Zaidi Falek , Clement Emily , Cinato Mathieu , Le Gonidec Sophie , Guérard Adrien , Lehuédé Camille , Garandeau David , Nieto Laurence , Renaud-Gabardos Edith , Prats Anne-Catherine , Valet Philippe , Malavaud Bernard , Muller Catherine
Published: April 2023

Abstract
Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an in vitro model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results.
Implications:
Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.
Data from Adipose-Derived VEGF–mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women
Authors: Sahoo Subhransu S. , Lombard Janine M. , Ius Yvette , O'Sullivan Rachel , Wood Lisa G. , Nahar Pravin , Jaaback Kenneth , Tanwar Pradeep S.
Published: April 2023

Abstract
Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.

Implications: Adipocyte-derived VEGF–mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309–21. ©2017 AACR.
Data from Suppression of Breast Cancer Stem Cells and Tumor Growth by the RUNX1 Transcription Factor
Authors: Hong Deli , Fritz Andrew J. , Finstad Kristiaan H. , Fitzgerald Mark P. , Weinheimer Adam , Viens Adam L. , Ramsey Jon , Stein Janet L. , Lian Jane B. , Stein Gary S.
Published: April 2023

Abstract
Breast cancer remains the most common malignant disease in women worldwide. Despite advances in detection and therapies, studies are still needed to understand the mechanisms underlying this cancer. Cancer stem cells (CSC) play an important role in tumor formation, growth, drug resistance, and recurrence. Here, it is demonstrated that the transcription factor RUNX1, well known as essential for hematopoietic differentiation, represses the breast cancer stem cell (BCSC) phenotype and suppresses tumor growth in vivo. The current studies show that BCSCs sorted from premalignant breast cancer cells exhibit decreased RUNX1 levels, whereas ectopic expression of RUNX1 suppresses tumorsphere formation and reduces the BCSC population. RUNX1 ectopic expression in breast cancer cells reduces migration, invasion, and in vivo tumor growth (57%) in mouse mammary fat pad. Mechanistically, RUNX1 functions to suppress breast cancer tumor growth through repression of CSC activity and direct inhibition of ZEB1 expression. Consistent with these cellular and biochemical results, clinical findings using patient specimens reveal that the highest RUNX1 levels occur in normal mammary epithelial cells and that low RUNX1 expression in tumors is associated with poor patient survival.
Implications:
The key finding that RUNX1 represses stemness in several breast cancer cell lines points to the importance of RUNX1 in other solid tumors where RUNX1 may regulate CSC properties.
Data from Microenvironment-Derived Regulation of HIF Signaling Drives Transcriptional Heterogeneity in Glioblastoma Multiforme
Authors: Heiland Dieter Henrik , Gaebelein Annette , Börries Melanie , Wörner Jakob , Pompe Nils , Franco Pamela , Heynckes Sabrina , Bartholomae Mark , hAilín Darren Ó. , Carro Maria Stella , Prinz Marco , Weber Stefan , Mader Irina , Delev Daniel , Schnell Oliver
Published: April 2023

Abstract
The evolving and highly heterogeneous nature of malignant brain tumors underlies their limited response to therapy and poor prognosis. In addition to genetic alterations, highly dynamic processes, such as transcriptional and metabolic reprogramming, play an important role in the development of tumor heterogeneity. The current study reports an adaptive mechanism in which the metabolic environment of malignant glioma drives transcriptional reprogramming. Multiregional analysis of a glioblastoma patient biopsy revealed a metabolic landscape marked by varying stages of hypoxia and creatine enrichment. Creatine treatment and metabolism was further shown to promote a synergistic effect through upregulation of the glycine cleavage system and chemical regulation of prolyl-hydroxylase domain. Consequently, creatine maintained a reduction of reactive oxygen species and change of the α-ketoglutarate/succinate ratio, leading to an inhibition of HIF signaling in primary tumor cell lines. These effects shifted the transcriptional pattern toward a proneural subtype and reduced the rate of cell migration and invasion in vitro.

Implications: Transcriptional subclasses of glioblastoma multiforme are heterogeneously distributed within the same tumor. This study uncovered a regulatory function of the tumor microenvironment by metabolism-driven transcriptional reprogramming in infiltrating glioma cells. Mol Cancer Res; 16(4); 655–68. ©2018 AACR.
Data from In Situ Analysis of Mutant EGFRs Prevalent in Glioblastoma Multiforme Reveals Aberrant Dimerization, Activation, and Differential Response to Anti-EGFR Targeted Therapy
Authors: Gajadhar Aaron S. , Bogdanovic Elena , Muñoz Diana Marcela , Guha Abhijit
Published: April 2023

Abstract
Aberrations in epidermal growth factor receptor (EGFR/ErbB1) are the most common oncogenic alterations in glioblastoma multiforme (GBM), the most common primary brain tumor. Interactions between wild-type (wt) and mutant EGFRs and their subsequent activation are of biologic and potential therapeutic importance in GBMs. We recently showed that in situ proximity ligation assay (PLA) allows for quantitative evaluation of EGFR dimerization and activation in intact cells. Using this in situ platform, we show the aberrant homo-/heterodimeric properties of EGFRvIII and EGFRc958 mutants, the two most common EGFR mutants in GBMs. In addition, dimer phosphoactivation status could be detected by PLA with superior signal–noise ratio (>17-fold) and sensitivity (>16-fold) than immunofluorescence-based phospho-EGFR measurements. Dimer activation analysis indicated quantitative activation differences of mutant dimers. These aberrant features were not overexpression dependent but appeared independent of cellular expression levels, suggesting inherent properties of the mutant receptors. Moreover, we observed in situ detection of EGFRwt-EGFRvIII heterodimerization in GBM specimens, supporting our cell line observations. Notably, currently used anti-EGFR therapeutics, such as cetuximab, matuzumab, and panitumumab, could effectively block EGFRwt dimerization and activation but did not equally impair EGFRvIII homodimers, EGFRwt-EGFRvIII, or EGFRvIII-EGFRc958 heterodimers. EGFRvIII appears to have intrinsic phosphoactivation independent of dimerization as matuzumab blockade of homodimerization had no effect on receptor phosphorylation levels. These data suggest differences in the dimerization-blocking efficacy of EGFR monoclonal antibodies as mutant EGFR dimer configurations prevalent in GBMs can evade blockade by anti-EGFR treatments. Further studies are warranted to evaluate whether this evasion contributes to poor therapeutic response or resistance. Mol Cancer Res; 10(3); 428–40. ©2012 AACR.
Data from Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/NRAS/BRAFV600-Wild-Type Colorectal Cancer
Authors: Georgiou Alexandros , Stewart Adam , Cunningham David , Banerji Udai , Whittaker Steven R.
Published: April 2023

Abstract
Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600-wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600-wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies.
Implications:
This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/BRAFV600-wild-type tumors is warranted.
Data from RBM38 Is a Direct Transcriptional Target of E2F1 that Limits E2F1-Induced Proliferation
Authors: Feldstein Orit , Ben-Hamo Rotem , Bashari Dana , Efroni Sol , Ginsberg Doron
Published: April 2023

Abstract
The E2F family of transcription factors plays a pivotal role in the regulation of cell proliferation in higher eukaryotes and is a critical downstream target of the tumor suppressor pRB. The pRB/E2F pathway is defective in most human tumors, resulting in deregulated E2F activity that induces uncontrolled cell proliferation, a hallmark of tumor cells.

The RNA-binding protein RBM38, also named RNPC1, induces cell-cycle arrest in G1, at least in part, via binding to and stabilizing the mRNA of the cyclin-dependent kinase inhibitor p21. RBM38 levels are altered in human cancer. Generally, RBM38 is overexpressed in various tumors; however, RBM38 mRNA levels are reduced in some breast tumors due to increased methylation of its promoter region.

We show here that expression of RBM38 is regulated by E2F1. Specifically, RBM38 mRNA and protein levels are elevated upon activation of either exogenous E2F1 or endogenous E2Fs. Moreover, endogenous E2F1 binds the human RBM38 promoter and E2F1 knockdown reduces RBM38 levels. Our data raise the possibility that E2F1 together with E2F1-regulated RBM38 constitute a negative feedback loop that modulates E2F1 activity. In support of this, inhibition of RBM38 expression increases E2F1-mediated cell-cycle progression. Moreover, in human ovarian cancer, high correlation between expression of E2F1 and RBM38 is associated with increased survival.

Overall, our data identify RBM38 as novel transcriptional target of E2F1 that restricts E2F1-induced proliferation. Furthermore, this negative feedback loop seems to restrict tumor aggressiveness, thereby promoting survival of patients with cancer. Mol Cancer Res; 10(9); 1169–77. ©2012 AACR.
Data from Autophagy Induction Results in Enhanced Anoikis Resistance in Models of Peritoneal Disease
Authors: Chen James L. , David Jason , Cook-Spaeth Douglas , Casey Sydney , Cohen David , Selvendiran Karuppaiyah , Bekaii-Saab Tanios , Hays John L.
Published: April 2023

Abstract
Peritoneal carcinomatosis and peritoneal sarcomatosis is a potential complication of nearly all solid tumors and results in profoundly increased morbidity and mortality. Despite the ubiquity of peritoneal carcinomatosis/peritoneal sarcomatosis, there are no clinically relevant targeted therapies for either its treatment or prevention. To identify potential therapies, we developed in vitro models of peritoneal carcinomatosis/peritoneal sarcomatosis using tumor cell lines and patient-derived spheroids (PDS) that recapitulate anoikis resistance and spheroid proliferation across multiple cancer types. Epithelial- and mesenchymal-derived cancer cell lines (YOU, PANC1, HEYA8, CHLA10, and TC71) were used to generate spheroids and establish growth characteristics. Differential gene expression analyses of these spheroids to matched adherent cells revealed a consensus spheroid signature. This spheroid signature discriminates primary tumor specimens from tumor cells found in ascites of ovarian cancer patients and in our PDS models. Key in this gene expression signature is BNIP3 and BNIP3L, known regulators of autophagy and apoptosis. Elevated BNIP3 mRNA expression is associated with poor survival in ovarian cancer patients and elevated BNIP3 protein, as measured by IHC, and is also associated with higher grade tumors and shorter survival. Pharmacologic induction of autophagy with rapamycin significantly increased spheroid formation and survival while decreasing the induction of apoptosis. In contrast, the autophagy inhibitor hydroxychloroquine abrogated spheroid formation with a clear increase in apoptosis. Modulation of BNIP3 and the critical autophagy gene Beclin-1 (BECN1) also caused a significant decrease in spheroid formation. Combined, these data demonstrate how modulation of BNIP3-related autophagy, in PDS and in vitro spheroid models, alters the survival and morphology of spheroids.

Implications: Development of BNIP3/BNIP3L-targeting agents or autophagy-targeting agents may reduce morbidity and mortality associated with peritoneal carcinomatosis and sarcomatosis. Mol Cancer Res; 15(1); 26–34. ©2016 AACR.
Data from A Novel Zebrafish Model of Metastasis Identifies the HSD11β1 Inhibitor Adrenosterone as a Suppressor of Epithelial–Mesenchymal Transition and Metastatic Dissemination
Authors: Nakayama Joji , Lu Jeng-Wei , Makinoshima Hideki , Gong Zhiyuan
Published: April 2023

Abstract
Metastasis of cancer cells is multi-step process and dissemination is an initial step. Here we report a tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line as a new animal model for metastasis research, and demonstrate that this model can serve as a novel platform for discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of EGFR) transgenic zebrafish, which develops hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in 5 days through induction of an epithelial-to-mesenchymal transition. Using this model, we conducted in vivo drug screening and identified three hit drugs. One of them, adrenosterone, an inhibitor for hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), has a suppressor effect on cell dissemination in this model. Pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through downregulation of Snail and Slug, adrenosterone-treated cells recovered expression of E-cadherin and other epithelial markers and lost partial expression of mesenchymal markers compared with vehicle-treated cells. Taken together, our model offers a useful platform for the discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells.
Implications:
This study describes a transgenic zebrafish model for liver tumor metastasis and it has been successfully used for identification of some drugs to inhibit metastatic dissemination of human cancer cells.
Data from Metallothionein Induction by Hypoxia Involves Cooperative Interactions between Metal-Responsive Transcription Factor-1 and Hypoxia-Inducible Transcription Factor-1α
Authors: Murphy Brian J. , Kimura Tomoki , Sato Barbara G. , Shi Yihui , Andrews Glen K.
Published: April 2023

Abstract
Mammalian metallothionein (MT) genes are transcriptionally activated by the essential metal zinc as well as by environmental stresses, including toxic metal overload and redox fluctuations. In addition to playing a key role in zinc homeostasis, MT proteins can protect against metal- and oxidant-induced cellular damage, and may participate in other fundamental physiologic and pathologic processes such as cell survival, proliferation, and neoplasia. Previously, our group reported a requirement for metal-responsive transcription factor-1 (MTF-1) in hypoxia-induced transcription of mouse MT-I and human MT-IIA genes. Here, we provide evidence that the protumorigenic hypoxia-inducible transcription factor-1α (HIF-1α) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1α are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1α, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1α seems to function as a coactivator of MT-I gene transcription by interacting with MTF-1 during hypoxia. Coimmunoprecipitation studies suggest interaction between MTF-1 and HIF-1α, either directly or as mediated by other factors. It is proposed that association of these important transcription factors in a multiprotein complex represents a common strategy to control unique sets of hypoxia-inducible genes in both normal and diseased tissue. (Mol Cancer Res 2008;6(3):483–90)
Data 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

Abstract
DICER1 is essential for the generation of mature miRNAs and other short noncoding RNAs. Several lines of investigation implicate DICER1 as a tumor suppressor. Reduced DICER1 levels and changes in miRNA abundance have been associated with aggressive tumor phenotypes. The global effects of reduced DICER1 on mRNA transcript abundance in tumor cells remain largely unknown. We used short hairpin RNA to stably knock down DICER1 in endometrial cancer cell lines to begin to determine how reduced DICER1 activity contributes to tumor phenotypes. DICER1 knockdown did not affect cell proliferation but caused enhanced cell migration and growth in soft agar. miRNA and mRNA profiling in KLE cells revealed overall decreases in miRNA levels and changes in the relative abundance of many mRNAs. One of the most striking changes in mRNA levels was the upregulation of IFN-stimulated genes (ISG), the majority of which lack known miRNA target sequences. IFNβ, a key upstream regulator of the IFN response, was significantly increased in DICER1 knockdowns in the AN3CA, Ishikawa, and KLE endometrial cancer cell lines and in the normal endometrial cell line EM-E6/E7/TERT. IFNβ secreted in media from KLE and EM-E6/E7/TERT shDcr cells was sufficient to activate an IFN response in HT29 cells. The reduced miRNA processing in DICER1 knockdowns was associated with increases in pre-miRNAs in the cytoplasm. Our findings suggest that elevated pre-miRNA levels trigger the IFN response to double-stranded RNA. We thus report a novel effect of reduced DICER1 function in cancer cells. Mol Cancer Res; 10(3); 316–25. ©2012 AACR.
Data from Breast Field Cancerization: Isolation and Comparison of Telomerase-Expressing Cells in Tumor and Tumor Adjacent, Histologically Normal Breast Tissue
Authors: Trujillo Kristina A. , Hines William C. , Vargas Keith M. , Jones Anna C. , Joste Nancy E. , Bisoffi Marco , Griffith Jeffrey K.
Published: April 2023

Abstract
Telomerase stabilizes chromosomes by maintaining telomere length, immortalizes mammalian cells, and is expressed in more than 90% of human tumors. However, the expression of human telomerase reverse transcriptase (hTERT) is not restricted to tumor cells. We have previously shown that a subpopulation of human mammary epithelial cells (HMEC) in tumor-adjacent, histologically normal (TAHN) breast tissues expresses hTERT mRNA at levels comparable with levels in breast tumors. In the current study, we first validated a reporter for measuring levels of hTERT promoter activity in early-passage HMECs and then used this reporter to compare hTERT promoter activity in HMECs derived from tumor and paired TAHN tissues 1, 3, and 5 cm from the tumor (TAHN-1, TAHN-3, and TAHN-5, respectively). Cell sorting, quantitative real-time PCR, and microarray analyses showed that the 10% of HMECs with the highest hTERT promoter activity in both tumor and TAHN-1 tissues contain more than 95% of hTERT mRNA and overexpress many genes involved in cell cycle and mitosis. The percentage of HMECs within this subpopulation showing high hTERT promoter activity was significantly reduced or absent in TAHN-3 and TAHN-5 tissues. We conclude that the field of “normal tissue” proximal to the breast tumors contains a population of HMECs similar in hTERT expression levels and in gene expression to the HMECs within the tumor mass and that this population is significantly reduced in tissues more distal to the tumor. Mol Cancer Res; 9(9); 1209–21. ©2011 AACR.