Journal of Clinical Investigation -- Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter

Clin Invest. doi:10.1172/JCI36125.
Copyright © 2010, The American Society for Clinical Investigation.
Research Article
Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter
Adèle Hannigan1, Paul Smith2, Gabriela Kalna1, Cristiana Lo Nigro3, Clare Orange4, Darren I. O’Brien1, Reshma Shah2, Nelofer Syed2, Lindsay C. Spender1, Blanca Herrera1, Johanna K. Thurlow1, Laura Lattanzio3, Martino Monteverde3, Meghan E. Maurer5, Francesca M. Buffa6, Jelena Mann7, David C.K. Chu8, Catharine M.L. West9, Max Patridge10, Karin A. Oien4, Jonathan A. Cooper5, Margaret C. Frame11, Adrian L. Harris6, Louise Hiller12, Linda J. Nicholson13, Milena Gasco3, Tim Crook2 and Gareth J. Inman1

1The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom.
2Cancer Genetics and Epigenetics Laboratory, Breakthrough Breast Cancer, Institute for Cancer Research, London, United Kingdom.
3Department of Medical Oncology, Ospedale Santa Croce e Carle, Cuneo, Italy.
4Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
5Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
6Cancer Research UK (CRUK) Molecular Oncology Laboratories, The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
7Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
8The University of Georgia College of Pharmacy, Athens, Georgia, USA.
9Translational Radiobiology, School of Cancer and Enabling Sciences, Christie Hospital NHS Trust, Manchester, United Kingdom.
10Department of Oral and Maxillofacial Surgery, Kings College London, Guy’s, King’s and St. Thomas’ Hospitals, London, United Kingdom.
11Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
12Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom.
13King’s College London School of Medicine, Cancer Studies Division, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom.

Address correspondence to: Gareth J. Inman, Biomedical Research Institute, University of Dundee, Level 5, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom. Phone: 0044.1382.496696; Fax: 0044.1382.669993; E-mail: g.j.inman@dundee.ac.uk.

Published July 1, 2010
Received for publication September 29, 2009, and accepted in revised form May 12, 2010.

The cytokine TGF-β acts as a tumor suppressor in normal epithelial cells and during the early stages of tumorigenesis. During malignant progression, cancer cells can switch their response to TGF-β and use this cytokine as a potent oncogenic factor; however, the mechanistic basis for this is poorly understood. Here we demonstrate that downregulation of disabled homolog 2 (DAB2) gene expression via promoter methylation frequently occurs in human squamous cell carcinomas (SCCs) and acts as an independent predictor of metastasis and poor prognosis. Retrospective microarray analysis in an independent data set indicated that low levels of DAB2 and high levels of TGFB2 expression correlate with poor prognosis. Immunohistochemistry, reexpression, genetic knockout, and RNAi silencing studies demonstrated that downregulation of DAB2 expression modulated the TGF-β/Smad pathway. Simultaneously, DAB2 downregulation abrogated TGF-β tumor suppressor function, while enabling TGF-β tumor-promoting activities. Downregulation of DAB2 blocked TGF-β–mediated inhibition of cell proliferation and migration and enabled TGF-β to promote cell motility, anchorage-independent growth, and tumor growth in vivo. Our data indicate that DAB2 acts as a tumor suppressor by dictating tumor cell TGF-β responses, identify a biomarker for SCC progression, and suggest a means to stratify patients with advanced SCC who may benefit clinically from anti–TGF-β therapies.

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Journal of Clinical Investigation -- Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter