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PMID: 23307470 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

EMBO molecular medicine ·Vol. 5 ·No. 2 ·2013-02-00 ·Pages 264-79

Wend P, Runke S, Wend K, Anchondo B, Yesayan M, Jardon M, Hardie N, Loddenkemper C, Ulasov I, Lesniak MS, Wolsky R, Bentolila LA, Grant SG, Elashoff D, Lehr S, Latimer JJ, Bose S, Sattar H, Krum SA, Miranda-Carboni GA

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.

MeSH Terms
Animals Breast Neoplasms/genetics,metabolism,pathology,physiopathology Cell Line, Tumor Cell Proliferation Estrogen Receptor alpha/deficiency,genetics Female Gene Expression Regulation, Neoplastic HMGA2 Protein/genetics,metabolism Humans Mice Mice, Transgenic Neoplasm Metastasis Proto-Oncogene Proteins/genetics,metabolism Receptor, ErbB-2/deficiency,genetics Receptors, Progesterone/deficiency,genetics Up-Regulation Wnt Proteins/genetics,metabolism Wnt Signaling Pathway beta Catenin/genetics,metabolism
Chemicals
Estrogen Receptor alpha HMGA2 Protein Proto-Oncogene Proteins Receptors, Progesterone WNT10B protein, human Wnt Proteins beta Catenin Receptor, ErbB-2
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Wend Peter
Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
Runke Stephanie
Wend Korinna
Anchondo Brenda
Yesayan Maria
Jardon Meghan
Hardie Natalie
Loddenkemper Christoph
Ulasov Ilya
Lesniak Maciej S
Wolsky Rebecca
Bentolila Laurent A
Grant Stephen G
Elashoff David
Lehr Stephan
Latimer Jean J
Bose Shikha
Sattar Husain
Krum Susan A
Miranda-Carboni Gustavo A
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Article Info
Journal
EMBO molecular medicine
Abbr.
EMBO Mol Med
ISSN
1757-4684
DOI
10.1002/emmm.201201320
Published
2013-02-00
Epub
2013-00-11
Pages
264-79
Language
English
Region
England
NLM ID
101487380
PMCID
PMC3569642
Subset
IM
Grants
NCI NIH HHS · K22 CA137168 · United States
NICHD NIH HHS · K12 HD001400-08 · United States
NCATS NIH HHS · UL1 TR000124 · United States
NICHD NIH HHS · K12 HD001400 · United States
NIDDK NIH HHS · R56 DK090231 · United States
NCI NIH HHS · K22 CA137168-01A1 · United States
NIDDK NIH HHS · 1R56DK090231-01 · United States
NCATS NIH HHS · UL1 TR000005 · United States
NCATS NIH HHS · UL1TR000124 · United States
External Links
PubMed source DOI: 10.1002/emmm.201201320 PMC Full Text View journal details
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