title: GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation.
abstract: 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 α6β1 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 α6β1, establishing an autocrine loop. NRP2 can be targeted in vivo to retard tumour initiation. These findings reveal a novel autocrine pathway involving VEGF/NRP2, α6β1 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.
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA. hira.goel@umassmed.edu
authors: Hira Lal
authors: HL
authors: Goel
authors: Bryan
authors: B
authors: Pursell
authors: Cheng
authors: C
authors: Chang
authors: Leslie M
authors: LM
authors: Shaw
authors: Junhao
authors: J
authors: Mao
authors: Karl
authors: K
authors: Simin
authors: Prashant
authors: P
authors: Kumar
authors: Craig W
authors: CW
authors: Vander Kooi
authors: Leonard D
authors: LD
authors: Shultz
authors: Dale L
authors: DL
authors: Greiner
authors: Jens Henrik
authors: JH
authors: Norum
authors: Rune
authors: R
authors: Toftgard
authors: Charlotte
authors: C
authors: Kuperwasser
authors: Arthur M
authors: AM
authors: Mercurio
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039121:Integrin alpha6beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D039121:Integrin alpha6beta1; D039943:Neuropilin-2; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7