GLI1 regulates a novel neuropilin-2/alpha6beta1 integrin based autocrine pathway that contributes to breast cancer initiation
Authors
Goel, Hira LalPursell, Bryan M.
Chang, Cheng
Shaw, Leslie M.
Mao, Junhao
Simin, Karl
Kumar, Prashant
Vander Kooi, Craig W.
Shultz, Leonard D.
Greiner, Dale L.
Norum, Jens Henrik
Toftgard, Rune
Kuperwasser, Charlotte
Mercurio, Arthur M.
Document Type
Journal ArticlePublication Date
2013-04-01Keywords
Breast NeoplasmsOncogene Proteins
Trans-Activators
Neoplastic Stem Cells
UMCCTS funding
breast cancer
GLI1
integrin
neuropilin-2
stem cells
Amino Acids, Peptides, and Proteins
Cancer Biology
Cells
Investigative Techniques
Neoplasms
Skin and Connective Tissue Diseases
Therapeutics
Metadata
Show full item recordAbstract
The characterization of cells with tumour initiating potential is significant for advancing our understanding of cancer and improving therapy. Aggressive, triple-negative breast cancers (TNBCs) are enriched for tumour-initiating cells (TICs). We investigated that hypothesis that VEGF receptors expressed on TNBC cells mediate autocrine signalling that contributes to tumour initiation. We discovered the VEGF receptor neuropilin-2 (NRP2) is expressed preferentially on TICs, involved in the genesis of TNBCs and necessary for tumour initiation. The mechanism by which NRP2 signalling promotes tumour initiation involves stimulation of the alpha6beta1 integrin, focal adhesion kinase-mediated activation of Ras/MEK signalling and consequent expression of the Hedgehog effector GLI1. GLI1 also induces BMI-1, a key stem cell factor, and it enhances NRP2 expression and the function of alpha6beta1, establishing an autocrine loop. NRP2 can be targeted in vivo to retard tumour initiation. These findings reveal a novel autocrine pathway involving VEGF/NRP2, alpha6beta1 and GLI1 that contributes to the initiation of TNBC. They also support the feasibility of NRP2-based therapy for the treatment of TNBC that targets and impedes the function of TICs. of EMBO.Source
EMBO Mol Med. 2013 Apr;5(4):488-508. doi: 10.1002/emmm.201202078. Link to article on publisher's site
DOI
10.1002/emmm.201202078Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28853PubMed ID
23436775Related Resources
Rights
Copyright 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.ae974a485f413a2113503eed53cd6c53
10.1002/emmm.201202078