WNT10B/β‐catenin signalling induces HMGA2 and proliferation in metastatic triple‐negative breast cancer

EMBO Molecular Medicine

Peter Wend¹  Stephanie Runke¹  Korinna Wend⁷  Brenda Anchondo¹  Maria Yesayan¹  Meghan Jardon¹  Natalie Hardie¹  Christoph Loddenkemper⁵  Ilya Ulasov³  Maciej S. Lesniak³  Rebecca Wolsky⁴  Laurent A. Bentolila¹⁰  Stephen G. Grant²  David Elashoff⁹  Stephan Lehr⁶  Jean J. Latimer²  Shikha Bose^1,8  Husain Sattar⁴  Susan A. Krum⁷ 

[1] Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA;Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale-Davie, FL, USA;Department of Brain Tumor Biology, The University of Chicago, Chicago, IL, USA;Department of Pathology, The University of Chicago, Chicago, IL, USA;Institute of Pathology, Charité University Medicine/UKBF, Berlin, Germany;Baxter Innovations GmbH, Vienna, Austria;UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;Department of Biostatistics, UCLA School of Public Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA;California NanoSystems Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

关键词: cancer stem cells;    HMGA2;    metastasis;    triple negative breast cancer;    wnt signalling;   

DOI  :  10.1002/emmm.201201320

来源: Wiley

【 摘 要 】

Abstract

Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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