Article

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

Peter WendDepartment of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USAStephanie RunkeDepartment of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USAKorinna WendUCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USABrenda AnchondoDepartment of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USAMaria YesayanDepartment of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USAMeghan JardonDepartment of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USANatalie A. HardieDepartment of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USAChristoph LoddenkemperInstitute of Pathology, Charité University Medicine/UKBF, Berlin, GermanyIlya V. UlasovDepartment of Brain Tumor Biology, The University of Chicago, Chicago, IL, USAMaciej S. LesniakDepartment of Brain Tumor Biology, The University of Chicago, Chicago, IL, USARebecca J. WolskyDepartment of Pathology, The University of Chicago, Chicago, IL, USA;Laurent A. BentolilaCalifornia NanoSystems Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USAStephen G. GrantDepartment of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale-Davie, FL, USADavid ElashoffDepartment of Biostatistics, UCLA School of Public Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAStephan LehrBaxter Innovations GmbH, Vienna, AustriaJean J. LatimerDepartment of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale-Davie, FL, USAShikha BoseDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAHusain SattarDepartment of Pathology, The University of Chicago, Chicago, IL, USA;Susan A. KrumUCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USAGustavo A. Miranda‐CarboniDepartment of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

2013en

ABI

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.

Identifiers

DOI: 10.1002/emmm.201201320

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Cited by 20 references

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