bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure 2 from Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation
Authors: Le Scolan Erwan , Zhu Qingwei , Wang Long , Bandyopadhyay Abhik , Javelaud Delphine , Mauviel Alain , Sun LuZhe , Luo Kunxin
Published: March 2023

Supplementary Figure 2 from Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation
Supplementary Figure 1 from Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation
Authors: Le Scolan Erwan , Zhu Qingwei , Wang Long , Bandyopadhyay Abhik , Javelaud Delphine , Mauviel Alain , Sun LuZhe , Luo Kunxin
Published: March 2023

Supplementary Figure 1 from Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation
Supplementary Figure 8 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Authors: Mitsiades Constantine S. , Ocio Enrique M. , Pandiella Atanasio , Maiso Patricia , Gajate Consuelo , Garayoa Mercedes , Vilanova David , Montero Juan Carlos , Mitsiades Nicholas , McMullan Ciaran J. , Munshi Nikhil C. , Hideshima Teru , Chauhan Dharminder , Aviles Pablo , Otero Gabriel , Faircloth Glynn , Mateos M. Victoria , Richardson Paul G. , Mollinedo Faustino , San-Miguel Jesus F. , Anderson Kenneth C.
Published: March 2023

Supplementary Figure 8 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Supplementary Table 4 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Authors: Bonome Tomas , Levine Douglas A. , Shih Joanna , Randonovich Mike , Pise-Masison Cindy A. , Bogomolniy Faina , Ozbun Laurent , Brady John , Barrett J. Carl , Boyd Jeff , Birrer Michael J.
Published: March 2023

Supplementary Table 4 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Supplementary Figure 7 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Authors: Mitsiades Constantine S. , Ocio Enrique M. , Pandiella Atanasio , Maiso Patricia , Gajate Consuelo , Garayoa Mercedes , Vilanova David , Montero Juan Carlos , Mitsiades Nicholas , McMullan Ciaran J. , Munshi Nikhil C. , Hideshima Teru , Chauhan Dharminder , Aviles Pablo , Otero Gabriel , Faircloth Glynn , Mateos M. Victoria , Richardson Paul G. , Mollinedo Faustino , San-Miguel Jesus F. , Anderson Kenneth C.
Published: March 2023

Supplementary Figure 7 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Supplementary Table 3 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Authors: Bonome Tomas , Levine Douglas A. , Shih Joanna , Randonovich Mike , Pise-Masison Cindy A. , Bogomolniy Faina , Ozbun Laurent , Brady John , Barrett J. Carl , Boyd Jeff , Birrer Michael J.
Published: March 2023

Supplementary Table 3 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Supplementary Figure 5 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Authors: Mitsiades Constantine S. , Ocio Enrique M. , Pandiella Atanasio , Maiso Patricia , Gajate Consuelo , Garayoa Mercedes , Vilanova David , Montero Juan Carlos , Mitsiades Nicholas , McMullan Ciaran J. , Munshi Nikhil C. , Hideshima Teru , Chauhan Dharminder , Aviles Pablo , Otero Gabriel , Faircloth Glynn , Mateos M. Victoria , Richardson Paul G. , Mollinedo Faustino , San-Miguel Jesus F. , Anderson Kenneth C.
Published: March 2023

Supplementary Figure 5 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Supplementary Table 1 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Authors: Bonome Tomas , Levine Douglas A. , Shih Joanna , Randonovich Mike , Pise-Masison Cindy A. , Bogomolniy Faina , Ozbun Laurent , Brady John , Barrett J. Carl , Boyd Jeff , Birrer Michael J.
Published: March 2023

Supplementary Table 1 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Supplementary Figure 5 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Authors: Bonome Tomas , Levine Douglas A. , Shih Joanna , Randonovich Mike , Pise-Masison Cindy A. , Bogomolniy Faina , Ozbun Laurent , Brady John , Barrett J. Carl , Boyd Jeff , Birrer Michael J.
Published: March 2023

Supplementary Figure 5 from A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Supplementary Figure 2 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Authors: Mitsiades Constantine S. , Ocio Enrique M. , Pandiella Atanasio , Maiso Patricia , Gajate Consuelo , Garayoa Mercedes , Vilanova David , Montero Juan Carlos , Mitsiades Nicholas , McMullan Ciaran J. , Munshi Nikhil C. , Hideshima Teru , Chauhan Dharminder , Aviles Pablo , Otero Gabriel , Faircloth Glynn , Mateos M. Victoria , Richardson Paul G. , Mollinedo Faustino , San-Miguel Jesus F. , Anderson Kenneth C.
Published: March 2023

Supplementary Figure 2 from Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo
Supplementary Figures 1-5, Table 1 from DNA Damage Signaling in Hematopoietic Cells: A Role for Mre11 Complex Repair of Topoisomerase Lesions
Authors: Morales Monica , Liu Yan , Laiakis Evagelia C. , Morgan William F. , Nimer Stephen D. , Petrini John H.J.
Published: March 2023

Supplementary Figures 1-5, Table 1 from DNA Damage Signaling in Hematopoietic Cells: A Role for Mre11 Complex Repair of Topoisomerase Lesions
Supplementary Figure Legends 1-2 from αvβ6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation
Authors: Marsh Daniel , Dickinson Sarah , Neill Graham W. , Marshall John F. , Hart Ian R. , Thomas Gareth J.
Published: March 2023

Supplementary Figure Legends 1-2 from αvβ6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation
Supplementary Figure Legends 1-3 from The Polycomb Gene Product BMI1 Contributes to the Maintenance of Tumor-Initiating Side Population Cells in Hepatocellular Carcinoma
Authors: Chiba Tetsuhiro , Miyagi Satoru , Saraya Atsunori , Aoki Ryutaro , Seki Atsuyoshi , Morita Yohei , Yonemitsu Yutaka , Yokosuka Osamu , Taniguchi Hideki , Nakauchi Hiromitsu , Iwama Atsushi
Published: March 2023

Supplementary Figure Legends 1-3 from The Polycomb Gene Product BMI1 Contributes to the Maintenance of Tumor-Initiating Side Population Cells in Hepatocellular Carcinoma
Supplementary Table 1 from Defective Claudin-7 Regulation by Tcf-4 and Sox-9 Disrupts the Polarity and Increases the Tumorigenicity of Colorectal Cancer Cells
Authors: Darido Charbel , Buchert Michael , Pannequin Julie , Bastide Pauline , Zalzali Hassan , Mantamadiotis Theo , Bourgaux Jean-François , Garambois Véronique , Jay Philippe , Blache Philippe , Joubert Dominique , Hollande Frédéric
Published: March 2023

Supplementary Table 1 from Defective Claudin-7 Regulation by Tcf-4 and Sox-9 Disrupts the Polarity and Increases the Tumorigenicity of Colorectal Cancer Cells
Supplementary Figure 2 from The Polycomb Gene Product BMI1 Contributes to the Maintenance of Tumor-Initiating Side Population Cells in Hepatocellular Carcinoma
Authors: Chiba Tetsuhiro , Miyagi Satoru , Saraya Atsunori , Aoki Ryutaro , Seki Atsuyoshi , Morita Yohei , Yonemitsu Yutaka , Yokosuka Osamu , Taniguchi Hideki , Nakauchi Hiromitsu , Iwama Atsushi
Published: March 2023

Supplementary Figure 2 from The Polycomb Gene Product BMI1 Contributes to the Maintenance of Tumor-Initiating Side Population Cells in Hepatocellular Carcinoma
Supplementary Table 1 from EBV MicroRNAs in Primary Lymphomas and Targeting of CXCL-11 by ebv-mir-BHRF1-3
Authors: Xia Tianli , O'Hara Andrea , Araujo Iguaracyra , Barreto Jose , Carvalho Eny , Sapucaia Jose Bahia , Ramos Juan Carlos , Luz Estela , Pedroso Celia , Manrique Michele , Toomey Ngoc L. , Brites Carlos , Dittmer Dirk P. , Harrington William J.
Published: March 2023

Supplementary Table 1 from EBV MicroRNAs in Primary Lymphomas and Targeting of CXCL-11 by ebv-mir-BHRF1-3
Supplementary Table 3 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
Authors: Osada Hirotaka , Tomida Shuta , Yatabe Yasushi , Tatematsu Yoshio , Takeuchi Toshiyuki , Murakami Hideki , Kondo Yutaka , Sekido Yoshitaka , Takahashi Takashi
Published: March 2023

Supplementary Table 3 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
Supplementary Table 1 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
Authors: Osada Hirotaka , Tomida Shuta , Yatabe Yasushi , Tatematsu Yoshio , Takeuchi Toshiyuki , Murakami Hideki , Kondo Yutaka , Sekido Yoshitaka , Takahashi Takashi
Published: March 2023

Supplementary Table 1 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
Supplementary Table 5 from Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category
Authors: Joensuu Emmi I. , Abdel-Rahman Wael M. , Ollikainen Miina , Ruosaari Salla , Knuutila Sakari , Peltomäki Päivi
Published: March 2023

Supplementary Table 5 from Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category
Supplementary Figures 1-3 from Diagnostic and Prognostic MicroRNAs in Stage II Colon Cancer
Authors: Schepeler Troels , Reinert Jørgen T. , Ostenfeld Marie S. , Christensen Lise L. , Silahtaroglu Asli N. , Dyrskjøt Lars , Wiuf Carsten , Sørensen Frank J. , Kruhøffer Mogens , Laurberg Søren , Kauppinen Sakari , Ørntoft Torben F. , Andersen Claus L.
Published: March 2023

Supplementary Figures 1-3 from Diagnostic and Prognostic MicroRNAs in Stage II Colon Cancer
Supplementary Methods and Figure 1 from The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib
Authors: Carew Jennifer S. , Nawrocki Steffan T. , Reddy Venudhar K. , Bush Dorothy , Rehg Jerold E. , Goodwin Andrew , Houghton Janet A. , Casero Robert A. , Marton Laurence J. , Cleveland John L.
Published: March 2023

Supplementary Methods and Figure 1 from The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib
Supplementary Text 4 from Cell Lineage Analysis of a Mouse Tumor
Authors: Frumkin Dan , Wasserstrom Adam , Itzkovitz Shalev , Stern Tomer , Harmelin Alon , Eilam Raya , Rechavi Gideon , Shapiro Ehud
Published: March 2023

Supplementary Text 4 from Cell Lineage Analysis of a Mouse Tumor
Supplementary Table 3 from Cell Lineage Analysis of a Mouse Tumor
Authors: Frumkin Dan , Wasserstrom Adam , Itzkovitz Shalev , Stern Tomer , Harmelin Alon , Eilam Raya , Rechavi Gideon , Shapiro Ehud
Published: March 2023

Supplementary Table 3 from Cell Lineage Analysis of a Mouse Tumor
Supplementary Figure 4 from Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-Like Protein 2, in Ovarian Cancer
Authors: Kikuchi Ryoko , Tsuda Hitoshi , Kozaki Ken-ichi , Kanai Yae , Kasamatsu Takahiro , Sengoku Kazuo , Hirohashi Setsuo , Inazawa Johji , Imoto Issei
Published: March 2023

Supplementary Figure 4 from Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-Like Protein 2, in Ovarian Cancer
Supplementary Figure 2 from Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-Like Protein 2, in Ovarian Cancer
Authors: Kikuchi Ryoko , Tsuda Hitoshi , Kozaki Ken-ichi , Kanai Yae , Kasamatsu Takahiro , Sengoku Kazuo , Hirohashi Setsuo , Inazawa Johji , Imoto Issei
Published: March 2023

Supplementary Figure 2 from Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-Like Protein 2, in Ovarian Cancer
Supplementary Figure 2 from Subtypes of Breast Cancer Show Preferential Site of Relapse
Authors: Smid Marcel , Wang Yixin , Zhang Yi , Sieuwerts Anieta M. , Yu Jack , Klijn Jan G.M. , Foekens John A. , Martens John W.M.
Published: March 2023

Supplementary Figure 2 from Subtypes of Breast Cancer Show Preferential Site of Relapse
Supplementary Table 1 from Semaphorin 3B Inhibits the Phosphatidylinositol 3-Kinase/Akt Pathway through Neuropilin-1 in Lung and Breast Cancer Cells
Authors: Castro-Rivera Emely , Ran Sophia , Brekken Rolf A. , Minna John D.
Published: March 2023

Supplementary Table 1 from Semaphorin 3B Inhibits the Phosphatidylinositol 3-Kinase/Akt Pathway through Neuropilin-1 in Lung and Breast Cancer Cells
Supplementary Figure 3 from Curcumin Blocks RON Tyrosine Kinase–Mediated Invasion of Breast Carcinoma Cells
Authors: Narasimhan Madhusudhanan , Ammanamanchi Sudhakar
Published: March 2023

Supplementary Figure 3 from Curcumin Blocks RON Tyrosine Kinase–Mediated Invasion of Breast Carcinoma Cells
Supplementary Figure 2 from Curcumin Blocks RON Tyrosine Kinase–Mediated Invasion of Breast Carcinoma Cells
Authors: Narasimhan Madhusudhanan , Ammanamanchi Sudhakar
Published: March 2023

Supplementary Figure 2 from Curcumin Blocks RON Tyrosine Kinase–Mediated Invasion of Breast Carcinoma Cells
Supplementary Table 1, Figures 1-5 from TGFBI Deficiency Predisposes Mice to Spontaneous Tumor Development
Authors: Zhang Ye , Wen Gengyun , Shao Genze , Wang Cuidong , Lin Chyuansheng , Fang Hongbo , Balajee Adayabalam S. , Bhagat Govind , Hei Tom K. , Zhao Yongliang
Published: March 2023

Supplementary Table 1, Figures 1-5 from TGFBI Deficiency Predisposes Mice to Spontaneous Tumor Development
Supplementary Movie 4 from The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Authors: Ambrogio Chiara , Voena Claudia , Manazza Andrea D. , Martinengo Cinzia , Costa Carlotta , Kirchhausen Tomas , Hirsch Emilio , Inghirami Giorgio , Chiarle Roberto
Published: March 2023

Supplementary Movie 4 from The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Supplementary Figure 2 from Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas
Authors: Dynek Jasmin N. , Chan Sara M. , Liu Jinfeng , Zha Jiping , Fairbrother Wayne J. , Vucic Domagoj
Published: March 2023

Supplementary Figure 2 from Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas
Supplementary Legends for Figures 1-7, Movies 1-6 from The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Authors: Ambrogio Chiara , Voena Claudia , Manazza Andrea D. , Martinengo Cinzia , Costa Carlotta , Kirchhausen Tomas , Hirsch Emilio , Inghirami Giorgio , Chiarle Roberto
Published: March 2023

Supplementary Legends for Figures 1-7, Movies 1-6 from The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Supplementary Figure 2: Revised May 4, 2009 from The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Authors: Ambrogio Chiara , Voena Claudia , Manazza Andrea D. , Martinengo Cinzia , Costa Carlotta , Kirchhausen Tomas , Hirsch Emilio , Inghirami Giorgio , Chiarle Roberto
Published: March 2023

Supplementary Figure 2: Revised May 4, 2009 from The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Supplementary Table 1 from MS4A12 Is a Colon-Selective Store-Operated Calcium Channel Promoting Malignant Cell Processes
Authors: Koslowski Michael , Sahin Ugur , Dhaene Karl , Huber Christoph , Türeci Özlem
Published: March 2023

Supplementary Table 1 from MS4A12 Is a Colon-Selective Store-Operated Calcium Channel Promoting Malignant Cell Processes
Supplementary Figure 1 from MS4A12 Is a Colon-Selective Store-Operated Calcium Channel Promoting Malignant Cell Processes
Authors: Koslowski Michael , Sahin Ugur , Dhaene Karl , Huber Christoph , Türeci Özlem
Published: March 2023

Supplementary Figure 1 from MS4A12 Is a Colon-Selective Store-Operated Calcium Channel Promoting Malignant Cell Processes
Supplementary Figure 3 from Quantitative Analysis of DNA Methylation Profiles in Lung Cancer Identifies Aberrant DNA Methylation of Specific Genes and Its Association with Gender and Cancer Risk Factors
Authors: Vaissière Thomas , Hung Rayjean J. , Zaridze David , Moukeria Anush , Cuenin Cyrille , Fasolo Virginie , Ferro Gilles , Paliwal Anupam , Hainaut Pierre , Brennan Paul , Tost Jörg , Boffetta Paolo , Herceg Zdenko
Published: March 2023

Supplementary Figure 3 from Quantitative Analysis of DNA Methylation Profiles in Lung Cancer Identifies Aberrant DNA Methylation of Specific Genes and Its Association with Gender and Cancer Risk Factors
Supplementary Figure 1 from Quantitative Analysis of DNA Methylation Profiles in Lung Cancer Identifies Aberrant DNA Methylation of Specific Genes and Its Association with Gender and Cancer Risk Factors
Authors: Vaissière Thomas , Hung Rayjean J. , Zaridze David , Moukeria Anush , Cuenin Cyrille , Fasolo Virginie , Ferro Gilles , Paliwal Anupam , Hainaut Pierre , Brennan Paul , Tost Jörg , Boffetta Paolo , Herceg Zdenko
Published: March 2023

Supplementary Figure 1 from Quantitative Analysis of DNA Methylation Profiles in Lung Cancer Identifies Aberrant DNA Methylation of Specific Genes and Its Association with Gender and Cancer Risk Factors
Data from Castration-Induced Downregulation of SPARC in Stromal Cells Drives Neuroendocrine Differentiation of Prostate Cancer
Authors: Enriquez Claudia , Cancila Valeria , Ferri Renata , Sulsenti Roberta , Fischetti Irene , Milani Matteo , Ostano Paola , Gregnanin Ilaria , Mello-Grand Maurizia , Berrino Enrico , Bregni Marco , Renne Giuseppe , Tripodo Claudio , Colombo Mario P. , Jachetti Elena
Published: March 2023

Abstract
Fatal neuroendocrine differentiation (NED) of castration-resistant prostate cancer is a recurrent mechanism of resistance to androgen deprivation therapies (ADT) and antiandrogen receptor pathway inhibitors (ARPI) in patients. The design of effective therapies for neuroendocrine prostate cancer (NEPC) is complicated by limited knowledge of the molecular mechanisms governing NED. The paucity of acquired genomic alterations and the deregulation of epigenetic and transcription factors suggest a potential contribution from the microenvironment. In this context, whether ADT/ARPI induces stromal cells to release NED-promoting molecules and the underlying molecular networks are unestablished. Here, we utilized transgenic and transplantable mouse models and coculture experiments to unveil a novel tumor-stroma cross-talk that is able to induce NED under the pressure of androgen deprivation. Castration induced upregulation of GRP78 in tumor cells, which triggers miR29-b–mediated downregulation of the matricellular protein SPARC in the nearby stroma. SPARC downregulation enabled stromal cells to release IL6, a known inducer of NED. A drug that targets GRP78 blocked NED in castrated mice. A public, human NEPC gene expression dataset showed that Hspa5 (encoding for GRP78) positively correlates with hallmarks of NED. Finally, prostate cancer specimens from patients developing local NED after ADT showed GRP78 upregulation in tumor cells and SPARC downregulation in the stroma. These results point to GRP78 as a potential therapeutic target and to SPARC downregulation in stromal cells as a potential early biomarker of tumors undergoing NED.
Significance:
Tumor–stroma cross-talk promotes neuroendocrine differentiation in prostate cancer in response to hormone therapy via a GRP78/SPARC/IL6 axis, providing potential therapeutic targets and biomarkers for neuroendocrine prostate cancer.
Data from AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis
Authors: Sun Yu , Li Xin , Yin Chengqian , Zhang Judy , Liang Ershang , Wu Xianfang , Ni Ying , Arbesman Joshua , Goding Colin R. , Chen Shuyang
Published: March 2023

Abstract
Inherited genetic variations in the melanocortin-1 receptor (MC1R) responsible for human red hair color (RHC) variants are associated with impaired DNA damage repair and increased melanoma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase zinc finger DHHC-type palmitoyltransferase 13 (ZDHHC13). A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in redheads. Here, we report that AMP-activated protein kinase (AMPK) phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in redheads. Consequently, phosphorylation of ZDHHC13 by AMPK increased MC1R-RHC downstream signaling. AMPK activation and MC1R palmitoylation repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in vivo in C57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R signaling was validated in human melanomas where AMPK upregulation correlated with expression of factors downstream from MC1R signaling and with prolonged patient survival. These findings suggest AMPK activation as a promising strategy to reduce melanoma risk, especially for individuals with red hair.
Significance:
Phosphorylation of ZDHHC13 by AMPK at S208 promotes MC1R activation and suppresses melanocyte transformation, indicating activation of AMPK as a potential approach to prevent melanoma in people with red hair.
Data from High-Density Single Nucleotide Polymorphism Array Defines Novel Stage and Location-Dependent Allelic Imbalances in Human Bladder Tumors
Authors: Koed Karen , Wiuf Carsten , Christensen Lise-Lotte , Wikman Friedrik P. , Zieger Karsten , Møller Klaus , von der Maase Hans , Ørntoft Torben F.
Published: March 2023

Abstract
Bladder cancer is a common disease characterized by multiple recurrences and an invasive disease course in more than 10% of patients. It is of monoclonal or oligoclonal origin and genomic instability has been shown at certain loci. We used a 10,000 single nucleotide polymorphism (SNP) array with an average of 2,700 heterozygous SNPs to detect allelic imbalances (AI) in 37 microdissected bladder tumors from 17 patients. Eight tumors represented upstaging from Ta to T1, eight from T1 to T2+, and one from Ta to T2+. The AI was strongly stage-dependent as four chromosomal arms showed AI in > 50% of Ta samples, eight in T1, and twenty-two in T2+ samples. The tumors showed stage-dependent clonality as 61.3% of AIs were reconfirmed in later T1 tumors and 84.4% in muscle-invasive tumors. Novel unstable chromosomal areas were identified at chromosomes 6q, 10p, 16q, 20p, 20q, and 22q. The tumors separated into two distinct groups, highly stable tumors (all Ta tumors) and unstable tumors (2/3 muscle-invasive). All 11 unstable tumors had lost chromosome 17p areas and 90% chromosome 8 areas affecting Netrin-1/UNC5D/MAP2K4 genes as well as others. AI was present at the TP53 locus in 10 out of 11 unstable tumors, whereas 6 had homozygous TP53 mutations. Tumor distribution pattern reflected AI as seven out of eight patients with additional upper urinary tract tumors had genomic stable bladder tumors (P < 0.05). These data show the power of high-resolution SNP arrays for defining clinically relevant AIs.
Data from Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
Authors: Leu Yu-Wei , Yan Pearlly S. , Fan Meiyun , Jin Victor X. , Liu Joseph C. , Curran Edward M. , Welshons Wade V. , Wei Susan H. , Davuluri Ramana V. , Plass Christoph , Nephew Kenneth P. , Huang Tim H-M.
Published: March 2023

Abstract
Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) α signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ERα target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ERα signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ERα targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ERα target genes, providing new direction for research in this classical signaling pathway.
Data from Immunoprevention of HER-2/neu Transgenic Mammary Carcinoma through an Interleukin 12-Engineered Allogeneic Cell Vaccine
Authors: De Giovanni Carla , Nicoletti Giordano , Landuzzi Lorena , Astolfi Annalisa , Croci Stefania , Comes Alberto , Ferrini Silvano , Meazza Raffaella , Iezzi Manuela , Di Carlo Emma , Musiani Piero , Cavallo Federica , Nanni Patrizia , Lollini Pier-Luigi
Published: March 2023

Abstract
This study evaluated the ability of cytokine-engineered allogeneic (H-2q) HER-2/neu-positive cells to prevent tumor development in mammary cancer-prone virgin female BALB/c (H-2d) mice transgenic for the transforming rat HER-2/neu oncogene (BALB-neuT mice). Repeated vaccinations with cells engineered to release interleukin (IL)-2, IL-12, IL-15, or IFN-γ showed that IL-12-engineered cell vaccines had the most powerful immunopreventive activity, with >80% of 1-year-old BALB-neuT mice free of tumors. On the contrary all of the untreated mice and all of the mice vaccinated with IL-12-engineered cells lacking either HER-2/neu or allogeneic antigens developed mammary carcinomas within 22 or 33 weeks, respectively. Whole mount, histology, immunohistochemistry, and gene expression profile analysis showed that vaccination with IL-12-engineered cells maintained 26-week mammary glands free of neoplastic growth, with a gene expression profile that clustered with that of untreated preneoplastic glands. The IL-12-engineered cell vaccine elicited a high production of IFN-γ and IL-4 and a strong anti-HER-2/neu antibody response. Immune protection was lost or markedly impaired in BALB-neuT mice lacking IFN-γ or antibody production, respectively. The protection afforded by the IL-12-engineered cell vaccine was equal to that provided by the systemic administration of recombinant IL-12 in combination with HER-2/neu H-2q cell vaccine. However, IL-12-engineered cell vaccine induced much lower circulating IL-12 and IFN-γ, and therefore lower potential side effects and systemic toxicity.
Data from Lysyl Oxidase Is a Tumor Suppressor Gene Inactivated by Methylation and Loss of Heterozygosity in Human Gastric Cancers
Authors: Kaneda Atsushi , Wakazono Kuniko , Tsukamoto Tetsuya , Watanabe Naoko , Yagi Yukiko , Tatematsu Masae , Kaminishi Michio , Sugimura Takashi , Ushijima Toshikazu
Published: March 2023

Abstract
Lysyl oxidase (LOX) and HRAS-like suppressor (HRASLS) are silenced in human gastric cancers and are reported to have growth-suppressive activities in ras-transformed mouse/rat fibroblasts. Here, we analyzed whether or not LOX and HRASLS are tumor suppressor genes in human gastric cancers. Loss of heterozygosity and promoter methylation of LOX were detected in 33% (9 of 27) and 27% (26 of 96) of gastric cancers, respectively. Biallelic methylation and loss of heterozygosity with promoter methylation were also demonstrated in gastric cancers. Silencing of LOX was also observed in colon, lung, and ovarian cancer cell lines. As for mutations, only one possible somatic mutation was found by analysis of 96 gastric cancer samples and 58 gastric and other cancer cell lines. When LOX was introduced into a gastric cancer cell line, MKN28, in which LOX and HRASLS were silenced, it reduced the number of anchorage-dependent colonies to 57 to 61%, and the number of anchorage-independent colonies to 11 to 23%. Sizes of tumors formed in nude mice were reduced to 19 to 26%. Growth suppression in soft agar assay was also observed in another gastric cancer cell line, KATOIII. On the other hand, neither loss of heterozygosity nor a somatic mutation was detected in HRASLS, and its introduction into MKN28 did not suppress the growth in vitro or in vivo. These data showed that LOX is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in gastric cancers, and possibly also in other cancers.
Data from Evaluation of Human Thymidine Kinase 1 Substrates as New Candidates for Boron Neutron Capture Therapy
Authors: Al-Madhoun Ashraf S. , Johnsamuel Jayaseharan , Barth Rolf F. , Tjarks Werner , Eriksson Staffan
Published: March 2023

Abstract
Thymidine analogs containing o-carboranylalkyl groups at the 3-position were screened as potential substrates for human thymidine kinase 1 (TK1), an enzyme that is selectively expressed in a variety of rapidly proliferating cells, including tumor cells. On the basis of previous studies, 12 of these were identified as potential delivery agents for boron neutron capture therapy, a therapeutic method used for the treatment of high-grade brain tumors. Compound 4 with a pentylene spacer between the o-carborane cage and the thymidine scaffold and compound 10, which has an additional dihydroxypropyl substituent at the o-carborane cage, were the best substrates for TK1 with kcat/Km values of 27% and 36% relative to that of thymidine, respectively. These compounds showed partial competitive inhibition for thymidine phosphorylation by TK1. Neither compound was a substrate of recombinant human thymidine phosphorylase nor were their respective 5′-monophosphates substrates of 5′-deoxynucleotidase 1, thereby indicating potential in vivo stability. The octanol/water partition coefficient for compound 10 was 2.09, suggesting that it has excellent physiochemical properties for crossing the blood brain barrier and penetrating brain tissue. The in vitro cytotoxic effect of the 12 analogs was moderate to low in mammalian cell cultures with IC50 values between 10 and 160 μmol/L. Compounds 4 and 10 were taken up selectively and retained by the murine fibroblast L929 cell line, in contrast to its TK1-deficient variant. These findings suggest that compound 10 is a promising candidate for selective delivery of boron-10 to malignant cells, and additional in vivo studies are planned to evaluate it for boron neutron capture therapy of brain tumors.
Data from In vitro Activity of Bcr-Abl Inhibitors AMN107 and BMS-354825 against Clinically Relevant Imatinib-Resistant Abl Kinase Domain Mutants
Authors: O'Hare Thomas , Walters Denise K. , Stoffregen Eric P. , Jia Taiping , Manley Paul W. , Mestan Jürgen , Cowan-Jacob Sandra W. , Lee Francis Y. , Heinrich Michael C. , Deininger Michael W.N. , Druker Brian J.
Published: March 2023

Abstract
Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.
Data from MicroRNA Gene Expression Deregulation in Human Breast Cancer
Authors: Iorio Marilena V. , Ferracin Manuela , Liu Chang-Gong , Veronese Angelo , Spizzo Riccardo , Sabbioni Silvia , Magri Eros , Pedriali Massimo , Fabbri Muller , Campiglio Manuela , Ménard Sylvie , Palazzo Juan P. , Rosenberg Anne , Musiani Piero , Volinia Stefano , Nenci Italo , Calin George A. , Querzoli Patrizia , Negrini Massimo , Croce Carlo M.
Published: March 2023

Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leukemias, where miRNA signatures were associated with specific clinicobiological features. Here, we show that, compared with normal breast tissue, miRNAs are also aberrantly expressed in human breast cancer. The overall miRNA expression could clearly separate normal versus cancer tissues, with the most significantly deregulated miRNAs being mir-125b, mir-145, mir-21, and mir-155. Results were confirmed by microarray and Northern blot analyses. We could identify miRNAs whose expression was correlated with specific breast cancer biopathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index.
Data from Gene Expression Profiling in Uveal Melanoma Reveals Two Molecular Classes and Predicts Metastatic Death
Authors: Onken Michael D. , Worley Lori A. , Ehlers Justis P. , Harbour J. William
Published: March 2023

Abstract
Melanomas are notoriously difficult to classify because of a lack of discrete clinical and pathological stages. Here, we show that primary uveal melanomas surprisingly cluster into two distinct molecular classes based on gene expression profile. Genes that discriminate class 1 (low-grade) from class 2 (high-grade) include highly significant clusters of down-regulated genes on chromosome 3 and up-regulated genes on chromosome 8q, which is consistent with previous cytogenetic studies. A three-gene signature allows biopsy-size tumor samples to be assigned accurately to tumor classes using either array or PCR platforms. Most importantly, this molecular classification strongly predicts metastatic death and outperforms other clinical and pathological prognostic indicators. These studies offer new insights into melanoma pathogenesis, and they provide a practical foundation for effective clinical predictive testing.
Data from A Major Role for Mitotic cdc2 Kinase Inactivation in the Establishment of the Mitotic DNA Damage Checkpoint
Authors: Bayart Emilie , Grigorieva Olga , Leibovitch Serge , Onclercq-Delic Rosine , Amor-Guéret Mounira
Published: March 2023

Abstract
Cdc2 kinase is inactivated when DNA damage occurs during the spindle assembly checkpoint. Here, we show that the level of mitotic Bloom syndrome protein phosphorylation reflects the level of cdc2 activity. A complete inactivation of cdc2 by either introduction of DNA double-strand breaks or roscovitine treatment prevents exit from mitosis. Thus, mitotic cdc2 inactivation plays a major role in the establishment of the mitotic DNA damage checkpoint. In response to mitotic cdc2 inactivation, the M/G1 transition is delayed after releasing the drug block in nonmalignant cells, whereas tumor cells exit mitosis without dividing and rereplicate their DNA, which results in mitotic catastrophe. This opens the way for new chemotherapeutic strategies.
Data from Lack of p53 Ser389 Phosphorylation Predisposes Mice to Develop 2-Acetylaminofluorene–Induced Bladder Tumors but not Ionizing Radiation–Induced Lymphomas
Authors: Hoogervorst Esther M. , Bruins Wendy , Zwart Edwin , van Oostrom Conny Th.M. , van den Aardweg Gerard J. , Beems Rudolf B. , van den Berg Jolanda , Jacks Tyler , van Steeg Harry , de Vries Annemieke
Published: March 2023

Abstract
Cellular activity of the tumor suppressor protein p53 is primarily regulated by posttranslational modifications. Phosphorylation of the COOH terminus, including Ser389, is thought to result in a conformational change of the p53 protein, enhancing DNA binding and transcriptional activity. In vitro studies presented here show that, in addition to UV radiation, Ser389 is phosphorylated upon exposure to 2-acetylaminofluorene (2-AAF). Both agents induce bulky DNA adducts repaired by nucleotide excision repair (NER). In contrast, ionizing radiation, known to induce DNA damage not repaired by NER, does not result in Ser389 phosphorylation. Previously, we have shown that p53.S389A mutant mice, lacking the Ser389 phosphorylation site, are sensitive to developing UV-induced skin tumors. Here, we show that p53.S389A mice are also prone to developing 2-AAF–induced urinary bladder tumors, whereas no increased tumor response was found upon ionizing irradiation. These results provide evidence for our hypothesis that phosphorylation of Ser389 is important for activation of p53 to exert its function as a tumor suppressor not exclusively upon the presence of UV-induced DNA damage, but also upon exposure to other bulky adduct-inducing agents. Analysis of 2-AAF– and UV-induced tumors from p53.S389A mice revealed the presence of additional p53 mutations, indicating that lack of Ser389 phosphorylation by itself is not sufficient to abrogate p53 function in tumor suppression. In addition, analyses of skin tumors of p53.S389A mice revealed an interesting hotspot mutation previously found exclusively in NER-deficient mice and patients.
Data from Genome-Wide Analysis of Epigenetic Silencing Identifies BEX1 and BEX2 as Candidate Tumor Suppressor Genes in Malignant Glioma
Authors: Foltz Greg , Ryu Gi-Yung , Yoon Jae-Geun , Nelson Timothy , Fahey Jessica , Frakes Amanda , Lee Hwahyung , Field Lorie , Zander Kaitlin , Sibenaller Zita , Ryken Timothy C. , Vibhakar Rajeev , Hood Leroy , Madan Anup
Published: March 2023

Abstract
Promoter hypermethylation and histone deacetylation are common epigenetic mechanisms implicated in the transcriptional silencing of tumor suppressor genes in human cancer. We treated two immortalized glioma cell lines, T98 and U87, and 10 patient-derived primary glioma cell lines with trichostatin A (TSA), a histone deacetylase inhibitor, or 5-aza-2′-deoxycytidine (5-AzaC), a DNA methyltransferase inhibitor, to comprehensively identify the cohort of genes reactivated through the pharmacologic reversal of these distinct but related epigenetic processes. Whole-genome microarray analysis identified genes induced by TSA (653) or 5-AzaC treatment (170). We selected a subset of reactivated genes that were markedly induced (greater than two-fold) after treatment with either TSA or 5-AzaC in a majority of glioma cell lines but not in cultured normal astrocytes. We then characterized the degree of promoter methylation and transcriptional silencing of selected genes in histologically confirmed human tumor and nontumor brain specimens. We identified two novel brain expressed genes, BEX1 and BEX2, which were silenced in all tumor specimens and exhibited extensive promoter hypermethylation. Viral-mediated reexpression of either BEX1 or BEX2 led to increased sensitivity to chemotherapy-induced apoptosis and potent tumor suppressor effects in vitro and in a xenograft mouse model. Using an integrated approach, we have established a novel platform for the genome-wide screening of epigenetically silenced genes in malignant glioma. This experimental paradigm provides a powerful new method for the identification of epigenetically silenced genes with potential function as tumor suppressors, biomarkers for disease diagnosis and detection, and therapeutically reversible modulators of critical regulatory pathways important in glioma pathogenesis. (Cancer Res 2006; 66(13): 6665-74)
Data from Breast Cancer DNA Methylation Profiles in Cancer Cells and Tumor Stroma: Association with HER-2/neu Status in Primary Breast Cancer
Authors: Fiegl Heidi , Millinger Simone , Goebel Georg , Müller-Holzner Elisabeth , Marth Christian , Laird Peter W. , Widschwendter Martin
Published: March 2023

Abstract
The HER-2/neu gene is amplified and overexpressed in 20% to 30% of invasive breast carcinomas and is associated with increased metastatic potential and less tamoxifen sensitivity. We generated the DNA methylation profiles of 143 human breast tumors and found significant differences in HER-2/neu expression and DNA methylation of five genes. For three of these five genes [PGR (coding for the progesterone receptor), HSD17B4 (coding for type 4 17-β-hydroxysteroid dehydrogenase, an enzyme that mainly degrades active 17-β-estradiol into inactive metabolites), and CDH13 (coding for H-cadherin)] a higher prevalence of DNA methylation in HER-2/neu-positive cancers was confirmed in an independent set of microdissected primary breast cancers. DNA methylation was not only present in cancer cells but also in the tumor stroma fraction. Of the isolated fractions in HER-2/neu-positive versus -negative cancers, 27.1% versus 10.5%, respectively, showed DNA methylation of the five genes (P = 0.011, Fisher's exact test). In Her-2++/+++ breast cancers, HSD17B4 mRNA expression was inversely associated with HSD17B4 methylation (P = 0.04). These data support the view that in addition to HER-2/neu-associated signaling, epigenetic changes in cancer as well as in tumor stroma cells might attribute to the specific biological features of HER-2/neu-positive cancers. (Cancer Res 2006; 66(1): 29-33)
Data from Sequential Valproic Acid/All-trans Retinoic Acid Treatment Reprograms Differentiation in Refractory and High-Risk Acute Myeloid Leukemia
Authors: Cimino Giuseppe , Lo-Coco Francesco , Fenu Susanna , Travaglini Lorena , Finolezzi Erica , Mancini Marco , Nanni Mauro , Careddu Angela , Fazi Francesco , Padula Fabrizio , Fiorini Roberto , Aloe Spiriti Maria Antonietta , Petti Maria Concetta , Venditti Adriano , Amadori Sergio , Mandelli Franco , Pelicci Pier Giuseppe , Nervi Clara
Published: March 2023

Abstract
Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (≥50 μg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q− in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients. (Cancer Res 2006; 66(17): 8903-11)
Data from DDX3, a DEAD Box RNA Helicase with Tumor Growth–Suppressive Property and Transcriptional Regulation Activity of the p21waf1/cip1 Promoter, Is a Candidate Tumor Suppressor
Authors: Chao Chi-Hong , Chen Chun-Ming , Cheng Pei-Lin , Shih Jing-Wen , Tsou Ann-Ping , Wu Lee Yan-Hwa
Published: March 2023

Abstract
DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21waf1/cip1, a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p21waf1/cip1 expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on p21waf1/cip1 promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the −123 to −63 region, relative to the transcription start site of p21waf1/cip1 promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21waf1/cip1. To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in ∼58% to 73% of hepatoma specimens, which led to the reduction of p21waf1/cip1 expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in >70% of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21waf1/cip1 promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor. (Cancer Res 2006; 66(13): 6579-88)
Data from Circulating Tumor-Specific DNA: A Marker for Monitoring Efficacy of Adjuvant Therapy in Cancer Patients
Authors: Fiegl Heidi , Millinger Simone , Mueller-Holzner Elisabeth , Marth Christian , Ensinger Christian , Berger Andreas , Klocker Helmut , Goebel Georg , Widschwendter Martin
Published: March 2023

Abstract
Adjuvant systemic therapy (a strategy that targets potential disseminated tumor cells after complete removal of the tumor) has clearly improved survival of patients with cancer. To date, no tool is available to monitor efficacy of these therapies, unless distant metastases arise, a situation that unavoidably leads to death. We analyzed RASSF1A DNA methylation in pretherapeutic sera and serum samples collected 1 year after surgery from 148 patients with breast cancer who were receiving adjuvant tamoxifen; 19.6% and 22.3% of patients with breast cancer showed RASSF1A DNA methylation in their pretherapeutic and 1-year-after serum samples, respectively. RASSF1A methylation 1 year after primary surgery (and during adjuvant tamoxifen therapy) was an independent predictor of poor outcome, with a relative risk (95% confidence interval) for relapse of 5.1 (1.3-19.8) and for death of 6.9 (1.9-25.9). Measurement of serum DNA methylation allows adjuvant systemic treatment to be monitored for efficacy: disappearance of RASSF1A DNA methylation in serum throughout treatment with tamoxifen indicates a response, whereas persistence or new appearance means resistance to adjuvant tamoxifen treatment. It remains to be seen whether modifications made in adjuvant therapeutic strategies based on detection of circulating nucleic acids will improve survival as well as quality of life.