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For:	Xu XX, Yi T, Tang B, Lambeth JD. Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Oncogene 1998;16:1561-9. [PMID: 9569023 DOI: 10.1038/sj.onc.1201678] [Citation(s) in RCA: 99] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

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Cited by Other Article(s)

Shah NN, Dave BP, Shah KC, Shah DD, Maheshwari KG, Chorawala MR, Parekh PS, Jani M. Disabled-2, a versatile tissue matrix multifunctional scaffold protein with multifaceted signaling: Unveiling its potential in the cancer battle. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024;397:5533-5557. [PMID: 38502243 DOI: 10.1007/s00210-024-03037-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 03/01/2024] [Indexed: 03/21/2024]

Abstract

A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/β-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-β) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.

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Shah NN, Dave BP, Shah KC, Shah DD, Maheshwari KG, Chorawala MR. Disable 2, A Versatile Tissue Matrix Multifunctional Scaffold Protein with Multifaceted Signaling: Unveiling Role in Breast Cancer for Therapeutic Revolution. Cell Biochem Biophys 2024;82:501-520. [PMID: 38594547 DOI: 10.1007/s12013-024-01261-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2024] [Indexed: 04/11/2024]

Price ZK, Lokman NA, Yoshihara M, Kajiyama H, Oehler MK, Ricciardelli C. Disabled-2 (DAB2): A Key Regulator of Anti- and Pro-Tumorigenic Pathways. Int J Mol Sci 2022;24:ijms24010696. [PMID: 36614139 PMCID: PMC9821069 DOI: 10.3390/ijms24010696] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/03/2023] Open

Figliuolo da Paz V, Ghishan FK, Kiela PR. Emerging Roles of Disabled Homolog 2 (DAB2) in Immune Regulation. Front Immunol 2020;11:580302. [PMID: 33178208 PMCID: PMC7593574 DOI: 10.3389/fimmu.2020.580302] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/24/2020] [Indexed: 12/24/2022] Open

Marigo I, Trovato R, Hofer F, Ingangi V, Desantis G, Leone K, De Sanctis F, Ugel S, Canè S, Simonelli A, Lamolinara A, Iezzi M, Fassan M, Rugge M, Boschi F, Borile G, Eisenhaure T, Sarkizova S, Lieb D, Hacohen N, Azzolin L, Piccolo S, Lawlor R, Scarpa A, Carbognin L, Bria E, Bicciato S, Murray PJ, Bronte V. Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages. Cancer Discov 2020;10:1758-1773. [PMID: 32651166 DOI: 10.1158/2159-8290.cd-20-0036] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 06/08/2020] [Accepted: 07/06/2020] [Indexed: 11/16/2022]

Affiliation(s)

Ilaria Marigo Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.
Rosalinda Trovato Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
Francesca Hofer Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
Vincenzo Ingangi Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
Giacomo Desantis Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
Kevin Leone Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
Francesco De Sanctis Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
Stefano Ugel Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
Stefania Canè Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
Anna Simonelli Department of Medicine, Section of Immunology, University of Verona, Verona, Italy
Alessia Lamolinara Department of Medicine and Aging Science, Center for Advanced Studies and Technology (CAST), University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
Manuela Iezzi Department of Medicine and Aging Science, Center for Advanced Studies and Technology (CAST), University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
Matteo Fassan Department of Medicine-DIMED, University of Padova, Padova, Italy
Massimo Rugge Department of Medicine-DIMED, University of Padova, Padova, Italy
Federico Boschi Department of Computer Science, University of Verona, Verona, Italy
Giulia Borile Department of Physics and Astronomy "G. Galilei," University of Padova, Padova, Italy Institute of Pediatric Research Città della Speranza, Padova, Italy
Thomas Eisenhaure Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Siranush Sarkizova Broad Institute of MIT and Harvard, Cambridge, Massachusetts
David Lieb Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Nir Hacohen Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Luca Azzolin Department of Molecular Medicine, University of Padova, Padova, Italy
Stefano Piccolo Department of Molecular Medicine, University of Padova, Padova, Italy IFOM, The FIRC Institute for Molecular Oncology, Padova, Italy
Rita Lawlor ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
Aldo Scarpa ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy Department of Diagnostic and Public Health, University of Verona, Verona, Italy
Luisa Carbognin Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Roma, Italy
Emilio Bria Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Roma, Italy
Silvio Bicciato Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy
Peter J Murray Max Planck Institute for Biochemistry, Martinsried, Germany
Vincenzo Bronte Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.

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Ogbu SC, Musich PR, Zhang J, Yao ZQ, Howe PH, Jiang Y. The role of disabled-2 (Dab2) in diseases. Gene 2020;769:145202. [PMID: 33059028 DOI: 10.1016/j.gene.2020.145202] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/16/2020] [Accepted: 09/29/2020] [Indexed: 12/16/2022]

Itami Y, Miyake M, Ohnishi S, Tatsumi Y, Gotoh D, Hori S, Morizawa Y, Iida K, Ohnishi K, Nakai Y, Inoue T, Anai S, Tanaka N, Fujii T, Shimada K, Furuya H, Khadka VS, Deng Y, Fujimoto K. Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder. Diagnostics (Basel) 2020;10:E54. [PMID: 31968685 PMCID: PMC7168324 DOI: 10.3390/diagnostics10010054] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 01/14/2020] [Accepted: 01/17/2020] [Indexed: 12/14/2022] Open

Affiliation(s)

Yoshitaka Itami Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Makito Miyake Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Sayuri Ohnishi Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Yoshihiro Tatsumi Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Daisuke Gotoh Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Shunta Hori Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Yousuke Morizawa Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Kota Iida Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Kenta Ohnishi Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Yasushi Nakai Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Takeshi Inoue Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Satoshi Anai Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Nobumichi Tanaka Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)
Tomomi Fujii Department of Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan;
Keiji Shimada Department of Pathology, Nara City Hospital, 1-50-1 Higashi kidera-cho, Nara 630-8305, Japan;
Hideki Furuya Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
Vedbar S. Khadka Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA; (V.S.K.); (Y.D.)
Youping Deng Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA; (V.S.K.); (Y.D.)
Kiyohide Fujimoto Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; (Y.I.); (M.M.); (S.O.); (Y.T.); (D.G.); (S.H.); (Y.M.); (K.I.); (K.O.); (Y.N.); (T.I.); (S.A.); (N.T.)

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Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations. Cells 2019;8:cells8111345. [PMID: 31671891 PMCID: PMC6912373 DOI: 10.3390/cells8111345] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/24/2019] [Accepted: 10/25/2019] [Indexed: 12/11/2022] Open

Hocevar BA. Loss of Disabled-2 Expression in Pancreatic Cancer Progression. Sci Rep 2019;9:7532. [PMID: 31101868 PMCID: PMC6525241 DOI: 10.1038/s41598-019-43992-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 12/12/2018] [Indexed: 02/07/2023] Open

Honda A, Kita T, Seshadri SV, Misaki K, Ahmed Z, Ladbury JE, Richardson GP, Yonemura S, Ladher RK. FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia. Proc Natl Acad Sci U S A 2018;115:8388-8393. [PMID: 30061390 PMCID: PMC6099903 DOI: 10.1073/pnas.1719861115] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open

Wang WL, Chang WL, Yang HB, Wang YC, Chang IW, Lee CT, Chang CY, Lin JT, Sheu BS. Low disabled-2 expression promotes tumor progression and determines poor survival and high recurrence of esophageal squamous cell carcinoma. Oncotarget 2018;7:71169-71181. [PMID: 27036032 PMCID: PMC5342070 DOI: 10.18632/oncotarget.8460] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 02/24/2016] [Indexed: 11/25/2022] Open

Lin W, Wang W, Wang D, Ling W. Quercetin protects against atherosclerosis by inhibiting dendritic cell activation. Mol Nutr Food Res 2017;61. [PMID: 28457022 DOI: 10.1002/mnfr.201700031] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 03/29/2017] [Accepted: 04/11/2017] [Indexed: 12/16/2022]

Tao W, Moore R, Smith ER, Xu XX. Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice. Front Cell Dev Biol 2016;4:129. [PMID: 27933291 PMCID: PMC5122593 DOI: 10.3389/fcell.2016.00129] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 10/27/2016] [Indexed: 01/29/2023] Open

Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice. Sci Rep 2016;6:35947. [PMID: 27779214 PMCID: PMC5078790 DOI: 10.1038/srep35947] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 10/06/2016] [Indexed: 01/01/2023] Open

Tsai HJ, Tseng CP. The adaptor protein Disabled-2: new insights into platelet biology and integrin signaling. Thromb J 2016;14:28. [PMID: 27766054 PMCID: PMC5056475 DOI: 10.1186/s12959-016-0101-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open

Abstract

Multiple functions of platelets in various physiological and pathological conditions have prompted considerable attention on understanding how platelets are generated and activated. Of the adaptor proteins that are expressed in megakaryocytes and platelets, Disabled-2 (Dab2) has been demonstrated in the past decades as a key regulator of platelet signaling. Dab2 has two alternative splicing isoforms p82 and p59. However, the mode of Dab2’s action remains to be clearly defined. In this review, we highlight the current understanding of Dab2 expression and function in megakaryocytic differentiation, platelet activation and integrin signaling. Accordingly, Dab2 is upregulated when the human K562 cells, human CD34⁺ hematopoietic stem cells, and murine embryonic stem cells were undergone megakaryocytic differentiation. Appropriate level of Dab2 expression is essential for fate determination of mesodermal and megakaryocytic differentiation. Dab2 is also shown to regulate cell-cell and cell-fibrinogen adhesion, integrin αIIbβ3 activation, fibrinogen uptake, and intracellular signaling of the megakaryocytic cells. In human platelets, p82 is the sole Dab2 isoform present in the cytoplasm and α-granules. Dab2 is released from the α-granules and forms two pools of Dab2 on the outer surface of the platelet plasma membrane, one at the sulfatide-bound and the other at integrin αIIbβ3-bound forms. The balance between these two pools of Dab2 controls the extent of clotting reaction, platelet-fibrinogen interactions and outside-in signaling. In murine platelets, p59 is the only Dab2 isoform and is required for platelet aggregation, fibrinogen uptake, RhoA-ROCK activation, adenosine diphosphate release and integrin αIIbβ3 activation stimulated by low concentration of thrombin. As a result, the bleeding time is prolonged and thrombus formation is impaired for the megakaryocyte lineage-restricted Dab2 deficient mouse. Although discrepancies of Dab2 function and isoform expression are noted between human and murine platelets, the studies up-to-date define Dab2 playing a pivotal role in integrin signaling and platelet activation. With the new tools such as CRISPR and TALEN in the generation of genetically modified animals, the progress in gaining new insights into the functions of Dab2 in megakaryocyte and platelet biology is expected to accelerate.

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Lybbert J, Gullingsrud J, Chesnokov O, Turyakira E, Dhorda M, Guerin PJ, Piola P, Muehlenbachs A, Oleinikov AV. Abundance of megalin and Dab2 is reduced in syncytiotrophoblast during placental malaria, which may contribute to low birth weight. Sci Rep 2016;6:24508. [PMID: 27072056 PMCID: PMC4829923 DOI: 10.1038/srep24508] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 03/30/2016] [Indexed: 11/09/2022] Open

Disabled homolog 2 is required for migration and invasion of prostate cancer cells. Front Med 2015;9:312-21. [PMID: 26143155 DOI: 10.1007/s11684-015-0401-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 05/07/2015] [Indexed: 12/13/2022]

Ahmed MS, Byeon SE, Jeong Y, Miah MA, Salahuddin M, Lee Y, Park SS, Bae YS. Dab2, a negative regulator of DC immunogenicity, is an attractive molecular target for DC-based immunotherapy. Oncoimmunology 2015;4:e984550. [PMID: 25949867 DOI: 10.4161/2162402x.2014.984550] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Accepted: 11/02/2014] [Indexed: 12/28/2022] Open

Coon BG, DiRenzo DM, Konieczny SF, Aguilar RC. Epsins’ novel role in cancer cell invasion. Commun Integr Biol 2014. [DOI: 10.4161/cib.14129] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open

Hormonal induction and roles of Disabled-2 in lactation and involution. PLoS One 2014;9:e110737. [PMID: 25360623 PMCID: PMC4216001 DOI: 10.1371/journal.pone.0110737] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open

Gao S, Bajrami I, Verrill C, Kigozi A, Ouaret D, Aleksic T, Asher R, Han C, Allen P, Bailey D, Feller S, Kashima T, Athanasou N, Blay JY, Schmitz S, Machiels JP, Upile N, Jones TM, Thalmann G, Ashraf SQ, Wilding JL, Bodmer WF, Middleton MR, Ashworth A, Lord CJ, Macaulay VM. Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling. Cancer Res 2014;74:5866-77. [PMID: 25168481 DOI: 10.1158/0008-5472.can-14-0806] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]

Affiliation(s)

Shan Gao Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Ilirjana Bajrami Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
Clare Verrill Department of Cellular Pathology and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom
Asha Kigozi Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
Djamila Ouaret Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Tamara Aleksic Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Ruth Asher Department of Cellular Pathology and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom
Cheng Han Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Paul Allen Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom
Deborah Bailey Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom
Stephan Feller Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Takeshi Kashima Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Nicholas Athanasou Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, Department of Pathology, Nuffield Orthopaedic Centre, Oxford, United Kingdom
Jean-Yves Blay University Claude Bernard Lyon I, Centre Léon Bérard, Department of Medicine, Lyon, France
Sandra Schmitz Service d'oncologie médicale, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Jean-Pascal Machiels Service d'oncologie médicale, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Nav Upile Liverpool CR-UK Centre, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom
Terry M Jones Liverpool CR-UK Centre, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom
George Thalmann Department of Urology, Inselspital, Bern, Bern, Switzerland
Shazad Q Ashraf Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Jennifer L Wilding Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Walter F Bodmer Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Mark R Middleton Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, Liverpool, United Kingdom
Alan Ashworth Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
Christopher J Lord Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
Valentine M Macaulay Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, Liverpool, United Kingdom.

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Moore R, Cai KQ, Tao W, Smith ER, Xu XX. Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues. BMC DEVELOPMENTAL BIOLOGY 2013;13:39. [PMID: 24168030 PMCID: PMC3924344 DOI: 10.1186/1471-213x-13-39] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 10/25/2013] [Indexed: 11/10/2022]

Tumbarello DA, Kendrick-Jones J, Buss F. Myosin VI and its cargo adaptors - linking endocytosis and autophagy. J Cell Sci 2013;126:2561-70. [PMID: 23781020 DOI: 10.1242/jcs.095554] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open

Yang Y, Zhang Q, Xu F, Chang C, Li X. Aberrant promoter methylation of Dab2 gene in myelodysplastic syndrome. Eur J Haematol 2012;89:469-77. [PMID: 23005040 DOI: 10.1111/ejh.12014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2012] [Indexed: 01/08/2023]

Teckchandani A, Mulkearns EE, Randolph TW, Toida N, Cooper JA. The clathrin adaptor Dab2 recruits EH domain scaffold proteins to regulate integrin β1 endocytosis. Mol Biol Cell 2012;23:2905-16. [PMID: 22648170 PMCID: PMC3408417 DOI: 10.1091/mbc.e11-12-1007] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open

Feed-back regulation of disabled-2 (Dab2) p96 isoform for GATA-4 during differentiation of F9 cells. Biochem Biophys Res Commun 2012;421:591-8. [PMID: 22525672 DOI: 10.1016/j.bbrc.2012.04.051] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 04/10/2012] [Indexed: 11/20/2022]

Novel aspects of the apolipoprotein-E receptor family: regulation and functional role of their proteolytic processing. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s11515-011-1186-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]

Mulkearns EE, Cooper JA. FCH domain only-2 organizes clathrin-coated structures and interacts with Disabled-2 for low-density lipoprotein receptor endocytosis. Mol Biol Cell 2012;23:1330-42. [PMID: 22323290 PMCID: PMC3315808 DOI: 10.1091/mbc.e11-09-0812] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open

Cheong SM, Choi H, Hong BS, Gho YS, Han JK. Dab2 is pivotal for endothelial cell migration by mediating VEGF expression in cancer cells. Exp Cell Res 2012;318:550-7. [PMID: 22265793 DOI: 10.1016/j.yexcr.2012.01.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 01/05/2012] [Accepted: 01/07/2012] [Indexed: 01/30/2023]

Koral K, Erkan E. PKB/Akt partners with Dab2 in albumin endocytosis. Am J Physiol Renal Physiol 2012;302:F1013-24. [PMID: 22218591 DOI: 10.1152/ajprenal.00289.2011] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open

Ahn M, Oh H, Lee W, Kim H, Moon C, Shin T. Immunohistochemical studies on disabled-2 protein in the spinal cords of rats with experimental autoimmune encephalomyelitis. Brain Res 2011;1416:51-60. [PMID: 21890121 DOI: 10.1016/j.brainres.2011.08.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 07/18/2011] [Accepted: 08/04/2011] [Indexed: 11/15/2022]

Coon BG, Direnzo DM, Konieczny SF, Aguilar RC. Epsins' novel role in cancer cell invasion. Commun Integr Biol 2011;4:95-7. [PMID: 21509192 DOI: 10.4161/cib.4.1.14129] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Accepted: 11/05/2010] [Indexed: 12/27/2022] Open

Chetrit D, Barzilay L, Horn G, Bielik T, Smorodinsky NI, Ehrlich M. Negative regulation of the endocytic adaptor disabled-2 (Dab2) in mitosis. J Biol Chem 2010;286:5392-403. [PMID: 21097498 DOI: 10.1074/jbc.m110.161851] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open

Abstract

Mitotic cells undergo extensive changes in shape and size through the altered regulation and function of their membrane trafficking machinery. Disabled 2 (Dab2), a multidomain cargo-specific endocytic adaptor and a mediator of signal transduction, is a potential integrator of trafficking and signaling. Dab2 binds effectors of signaling and trafficking that localize to different intracellular compartments. Thus, differential localization is a putative regulatory mechanism of Dab2 function. Furthermore, Dab2 is phosphorylated in mitosis and is thus regulated in the cell cycle. However, a detailed description of the intracellular localization of Dab2 in the different phases of mitosis and an understanding of the functional consequences of its phosphorylation are lacking. Here, we show that Dab2 is progressively displaced from the membrane in mitosis. This phenomenon is paralleled by a loss of co-localization with clathrin. Both phenomena culminate in metaphase/anaphase and undergo partial recovery in cytokinesis. Treatment with 2-methoxyestradiol, which arrests cells at the spindle assembly checkpoint, induces the same effects observed in metaphase cells. Moreover, 2-methoxyestradiol also induced Dab2 phosphorylation and reduced Dab2/clathrin interactions, endocytic vesicle motility, clathrin exchange dynamics, and the internalization of a receptor endowed with an NPXY endocytic signal. Serine/threonine to alanine mutations, of residues localized to the central region of Dab2, attenuated its phosphorylation, reduced its membrane displacement, and maintained its endocytic abilities in mitosis. We propose that the negative regulation of Dab2 is part of an accommodation of the cell to the altered physicochemical conditions prevalent in mitosis, aimed at allowing endocytic activity throughout the cell cycle.

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Disabled-2 downregulation promotes epithelial-to-mesenchymal transition. Br J Cancer 2010;103:1716-23. [PMID: 21063401 PMCID: PMC2994233 DOI: 10.1038/sj.bjc.6605975] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open

Penheiter SG, Singh RD, Repellin CE, Wilkes MC, Edens M, Howe PH, Pagano RE, Leof EB. Type II transforming growth factor-beta receptor recycling is dependent upon the clathrin adaptor protein Dab2. Mol Biol Cell 2010;21:4009-19. [PMID: 20881059 PMCID: PMC2982134 DOI: 10.1091/mbc.e09-12-1019] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open

Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, O’Brien DI, Shah R, Syed N, Spender LC, Herrera B, Thurlow JK, Lattanzio L, Monteverde M, Maurer ME, Buffa FM, Mann J, Chu DC, West CM, Patridge M, Oien KA, Cooper JA, Frame MC, Harris AL, Hiller L, Nicholson LJ, Gasco M, Crook T, Inman GJ. Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter. J Clin Invest 2010;120:2842-57. [PMID: 20592473 PMCID: PMC2912175 DOI: 10.1172/jci36125] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2009] [Accepted: 05/12/2010] [Indexed: 12/22/2022] Open

Affiliation(s)

Adèle Hannigan The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Paul Smith The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Gabriela Kalna The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Cristiana Lo Nigro The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Clare Orange The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Darren I. O’Brien The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Reshma Shah The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Nelofer Syed The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Lindsay C. Spender The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Blanca Herrera The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Johanna K. Thurlow The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Laura Lattanzio The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Martino Monteverde The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Meghan E. Maurer The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Francesca M. Buffa The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Jelena Mann The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
David C.K. Chu The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Catharine M.L. West The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Max Patridge The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Karin A. Oien The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Jonathan A. Cooper The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Margaret C. Frame The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Adrian L. Harris The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Louise Hiller The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Linda J. Nicholson The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Milena Gasco The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Tim Crook The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Gareth J. Inman The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom. Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom. Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. The University of Georgia College of Pharmacy, Athens, Georgia, USA. Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom. Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom. Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom. King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom

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Tong JH, Ng DC, Chau SL, So KK, Leung PP, Lee TL, Lung RW, Chan MW, Chan AW, Lo KW, To KF. Putative tumour-suppressor gene DAB2 is frequently down regulated by promoter hypermethylation in nasopharyngeal carcinoma. BMC Cancer 2010;10:253. [PMID: 20525238 PMCID: PMC2891638 DOI: 10.1186/1471-2407-10-253] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Accepted: 06/03/2010] [Indexed: 11/10/2022] Open

Abstract

Background

Human Disabled-2 (DAB2), is a multi-function signalling molecule that it is frequently down-regulated in human cancers. We aimed to investigate the possible tumour suppressor effect of DAB2 in nasopharyngeal carcinoma (NPC).

Methods

We studied the expression of DAB2 in NPC cell lines, xenografts and primary tumour samples. The status of promoter methylation was assessed by methylation specific PCR and bisulfite sequencing. The functional role of DAB2 in NPC was investigated by re-introducing DAB2 expression into NPC cell line C666-1.

Results

Decrease or absent of DAB2 transcript was observed in NPC cell lines and xenografts. Loss of DAB2 protein expression was seen in 72% (33/46) of primary NPC as demonstrated by immunohistochemistry. Aberrant DAB2 promoter methylation was detected in 65.2% (30/46) of primary NPC samples by methylation specific PCR. Treatment of the DAB2 negative NPC cell line C666-1 with 5-aza-2'-deoxycytidine resulted in restoration of DAB2 expression in a dose-dependent manner. Overexpression of DAB2 in NPC cell line C666-1 resulted in reduced growth rate and 35% reduction in anchorage-dependent colony formation, and inhibition of serum-induced c-Fos expression compared to vector-transfected controls. Over expression of DAB2 resulted in alterations of multiple pathways as demonstrated by expression profiling and functional network analysis, which confirmed the role of DAB2 as an adaptor molecule involved in multiple receptor-mediated signalling pathways.

Conclusions

We report the frequent down regulation of DAB2 in NPC and the promoter hypermethylation contributes to the loss of expression of DAB2. This is the first study demonstrating frequent DAB2 promoter hypermethylation in human cancer. Our functional studies support the putative tumour suppressor effect of DAB2 in NPC cells.

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Huang CL, Cheng JC, Kitajima K, Nakano T, Yeh CF, Chong KY, Tseng CP. Disabled-2 is required for mesoderm differentiation of murine embryonic stem cells. J Cell Physiol 2010;225:92-105. [DOI: 10.1002/jcp.22200] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]

Sivaramakrishnan S, Spudich JA. Coupled myosin VI motors facilitate unidirectional movement on an F-actin network. ACTA ACUST UNITED AC 2009;187:53-60. [PMID: 19786577 PMCID: PMC2762089 DOI: 10.1083/jcb.200906133] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]

Teckchandani A, Toida N, Goodchild J, Henderson C, Watts J, Wollscheid B, Cooper JA. Quantitative proteomics identifies a Dab2/integrin module regulating cell migration. J Cell Biol 2009;186:99-111. [PMID: 19581412 PMCID: PMC2712992 DOI: 10.1083/jcb.200812160] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Accepted: 06/12/2009] [Indexed: 01/04/2023] Open

Lu Z, Bast RC. Tumor suppressor genes. Cancer Treat Res 2009;149:109-29. [PMID: 19763433 DOI: 10.1007/978-0-387-98094-2_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]

Feo F, Frau M, Pascale RM. Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. World J Gastroenterol 2008;14:6601-15. [PMID: 19034960 PMCID: PMC2773299 DOI: 10.3748/wjg.14.6601] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open

Calvisi DF, Pinna F, Pellegrino R, Sanna V, Sini M, Daino L, Simile MM, De Miglio MR, Frau M, Tomasi ML, Seddaiu MA, Muroni MR, Feo F, Pascale RM. Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control. Int J Cancer 2008;123:2057-64. [DOI: 10.1002/ijc.23720] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]

Orlandini M, Nucciotti S, Galvagni F, Bardelli M, Rocchigiani M, Petraglia F, Oliviero S. Morphogenesis of human endothelial cells is inhibited by DAB2 via Src. FEBS Lett 2008;582:2542-8. [PMID: 18582465 DOI: 10.1016/j.febslet.2008.06.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2008] [Revised: 05/29/2008] [Accepted: 06/13/2008] [Indexed: 12/17/2022]

Zhang H, Lee JM, Wang Y, Dong L, Ko KWS, Pelletier L, Yao Z. Mutational analysis of the FXNPXY motif within LDL receptor-related protein 1 (LRP1) reveals the functional importance of the tyrosine residues in cell growth regulation and signal transduction. Biochem J 2008;409:53-64. [PMID: 17908054 DOI: 10.1042/bj20071127] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]

Diwakar R, Pearson AL, Colville-Nash P, Baines DL, Dockrell MEC. Role played by disabled-2 in albumin induced MAP Kinase signalling. Biochem Biophys Res Commun 2007;366:675-80. [PMID: 18070591 DOI: 10.1016/j.bbrc.2007.11.171] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2007] [Accepted: 11/27/2007] [Indexed: 10/22/2022]

Karam JA, Shariat SF, Huang HY, Pong RC, Ashfaq R, Shapiro E, Lotan Y, Sagalowsky AI, Wu XR, Hsieh JT. Decreased DOC-2/DAB2 Expression in Urothelial Carcinoma of the Bladder. Clin Cancer Res 2007;13:4400-6. [PMID: 17671122 DOI: 10.1158/1078-0432.ccr-07-0287] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]

Abstract

PURPOSE

DOC-2/DAB2 (differentially expressed in ovarian carcinoma-2/disabled-2), a potential tumor suppressor gene, is underexpressed in several cancers. Little is known about the expression of this gene in urothelial carcinoma of the bladder (UCB). We profiled DOC-2/DAB2 expression in mouse and human normal and neoplastic urothelia.

EXPERIMENTAL DESIGN

Immunohistochemical staining for DOC-2/DAB2 was carried out on tissue specimens from two transgenic mouse models with urothelium-specific molecular alterations and on a tissue microarray containing cores from 9 normal controls, 44 patients who underwent transurethral resection of the bladder tumor (TURBT), 195 patients who underwent radical cystectomy for UCB, and 39 lymph nodes with metastatic UCB.

RESULTS

Normal mouse urothelium stained uniformly with DOC-2/DAB2. Weaker staining was observed in low-grade, superficial papillary bladder tumors from transgenic mice harboring constitutively active Ha-Ras, whereas carcinoma in situ-like lesions and high-grade bladder tumors from transgenic mice expressing a SV40 T antigen completely lacked DOC-2/DAB2 expression. In human tissues, DOC-2/DAB2 expression was decreased in 11% of normal bladder specimens, 59% of TURBT specimens, 65% of radical cystectomy specimens, and 77% of the metastatic lymph node specimens. Decreased DOC-2/DAB2 expression was associated with advanced pathologic stage (P = 0.023), lymph node metastases (P = 0.050), and lymphovascular invasion (P < 0.001). In univariable, but not in multivariable analysis, decreased DOC-2/DAB2 was associated with an increased probability of bladder cancer recurrence (log-rank test, P = 0.020) and bladder cancer-specific mortality (log-rank test, P = 0.023).

CONCLUSIONS

Decreased DOC-2/DAB2 expression seems to occur early in bladder tumorigenesis and becomes more prominent in advanced stages of UCB.

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Mikesch JH, Steffen B, Berdel WE, Serve H, Müller-Tidow C. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia 2007;21:1638-47. [PMID: 17554387 DOI: 10.1038/sj.leu.2404732] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]

Kumbar DH, VanBergen A, Ocampo C, Muangmingsuk S, Griffin AJ, Gupta M. Adapter molecule DOC-2 is differentially expressed in pressure and volume overload hypertrophy and inhibits collagen synthesis in cardiac fibroblasts. J Appl Physiol (1985) 2007;102:2024-32. [PMID: 17255372 DOI: 10.1152/japplphysiol.00924.2006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open

Abstract DOC-2 (differentially expressed in ovarian carcinoma) is involved in Ras-, β-integrin-, PKC-, and transforming growth factor-β-mediated cell signaling. These pathways are implicated in the accumulation of extracellular matrix proteins during progression of hypertrophy to heart failure; however, the role of DOC-2 in cardiac pathophysiology has never been examined. This study was undertaken to 1) analyze DOC-2 expression in primary cultures of cardiac fibroblasts and cardiac myocytes and in the heart following different types of hemodynamic overloads and 2) examine its role in growth factor-mediated ERK activation and collagen production. Pressure overload and volume overload were induced for 10 wk in Sprague-Dawley rats by aortic constriction and by aortocaval shunt, respectively. ANG II (0.3 mg·kg−1·day−1) was infused for 2 wk. Results showed that, compared with myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with ANG II and TPA resulted in increased expression of DOC-2. Overexpression of DOC-2 in cardiac fibroblasts led to inhibition of hypertrophy agonist-stimulated ERK activation and collagen expression. An inverse correlation between collagen and DOC-2 was observed in in vivo models of cardiac hypertrophy; in pressure overload and after ANG II infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in volume overload increased DOC-2 levels were accompanied by unchanged collagen mRNA. These data for the first time describe expression of DOC-2 in the heart and demonstrate its modulation by growth-promoting agents in cultured cardiac fibroblasts and in in vivo models of heart hypertrophy. Results suggest a role of DOC-2 in cardiac remodeling involving collagen expression during chronic hemodynamic overload. Collapse

Bagadi SAR, Prasad CP, Srivastava A, Prashad R, Gupta SD, Ralhan R. Frequent loss of Dab2 protein and infrequent promoter hypermethylation in breast cancer. Breast Cancer Res Treat 2006;104:277-86. [PMID: 17115114 DOI: 10.1007/s10549-006-9422-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2006] [Accepted: 09/30/2006] [Indexed: 10/23/2022]