The embryonic transcription cofactor LBH is a direct target of the Wnt signaling pathway in epithelial development and in aggressive basal subtype breast cancers.
Affiliation
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.Issue Date
2010-09
Metadata
Show full item recordAbstract
Limb-bud and heart (LBH) is a novel key transcriptional regulator of vertebrate development. However, the molecular mechanisms upstream of LBH and its role in adult development are unknown. Here we show that in epithelial development, LBH expression is tightly controlled by Wnt signaling. LBH is transcriptionally induced by the canonical Wnt pathway, as evident by the presence of conserved functional T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) binding sites in the LBH locus and rapid beta-catenin-dependent upregulation of endogenous LBH by Wnt3a. In contrast, LBH induction by Wnt/beta-catenin signaling is inhibited by Wnt7a, which in limb development signals through a noncanonical pathway involving Lmx1b. Furthermore, we show that LBH is aberrantly overexpressed in mammary tumors of mouse mammary tumor virus (MMTV)-Wnt1-transgenic mice and in aggressive basal subtype human breast cancers that display Wnt/beta-catenin hyperactivation. Deregulation of LBH in human basal breast cancer appears to be Wnt/beta-catenin dependent, as DKK1 and Wnt7a inhibit LBH expression in breast tumor cells. Overexpression studies indicate that LBH suppresses mammary epithelial cell differentiation, an effect that could contribute to Wnt-induced tumorigenesis. Taken together, our findings link LBH for the first time to the Wnt signaling pathway in both development and cancer and highlight LBH as a potential new marker for therapeutically challenging basal-like breast cancers.Citation
The embryonic transcription cofactor LBH is a direct target of the Wnt signaling pathway in epithelial development and in aggressive basal subtype breast cancers. 2010, 30 (17):4267-79 Mol Cell BiolJournal
Molecular and Cellular BiologyDOI
10.1128/MCB.01418-09PubMed ID
20606007Type
ArticleLanguage
enISSN
1098-5549ae974a485f413a2113503eed53cd6c53
10.1128/MCB.01418-09
Scopus Count
Collections
Related articles
- Loss of Limb-Bud-and-Heart (LBH) attenuates mammary hyperplasia and tumor development in MMTV-Wnt1 transgenic mice.
- Authors: Ashad-Bishop K, Garikapati K, Lindley LE, Jorda M, Briegel KJ
- Issue date: 2019 Jan 8
- GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and β-catenin activity.
- Authors: Maric G, Annis MG, MacDonald PA, Russo C, Perkins D, Siwak DR, Mills GB, Siegel PM
- Issue date: 2019 Jun
- Redundant expression of canonical Wnt ligands in human breast cancer cell lines.
- Authors: Benhaj K, Akcali KC, Ozturk M
- Issue date: 2006 Mar
- A Wnt-ow of opportunity: targeting the Wnt/beta-catenin pathway in breast cancer.
- Authors: Prosperi JR, Goss KH
- Issue date: 2010 Sep
- Activation of the canonical WNT signaling pathway promotes ovarian surface epithelial proliferation without inducing β-catenin/Tcf-mediated reporter expression.
- Authors: Usongo M, Li X, Farookhi R
- Issue date: 2013 Mar