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.

The Transcription Factor GLI1 Interacts with SMAD Proteins to Modulate Transforming Growth Factor β-Induced Gene Expression in a p300/CREB-binding Protein-associated Factor (PCAF)-dependent Manner

“…These pathways modulate GLI1 activity mainly via regulation of the expression of this transcription factor (1,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Here, we provide evidence of a novel regulatory mechanism involving the interaction of components of the TGF␤ pathway (SMAD proteins) modulating GLI1 activity in cancer cells.…”

“…These findings support the notion that increased expression of GLI1 is sufficient for the development of a subset of tumors. GLI1 activity is regulated by different oncogenic cascades, including the HEDGEHOG, EGFR, RAS, and TGF␤ pathways (1,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). It has been demonstrated that malignant transformation induced by some of these cascades requires an intact GLI1 transcriptional activity (17,20,21).…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…In addition, CD49f cooperates with receptor tyrosine kinases to communicate, bidirectionally, between the cell and the extracellular matrix (ECM). Interestingly, however, the CD104 subunit appears to be expressed at very low levels, if at all in CSCs when compared to non-CSCs indicating that CD49fCD29 is the dominant integrin expressed by CSCs (81,82).…”

“…Although the CD29/CD49f integrins have been implicated in the function of BCSCs and other CSCs (81,82,93), much needs to be learned about the contribution of these integrins to the genesis of BCSCs. It has been shown that CD49f and CD29 contribute to therapy resistance, tumor relapse and metastasis in breast cancer.…”

Promotion of metastasis of thyroid cancer cells via NRP-2-mediated induction

“…To evaluate more rigorously the role of NRP-2 in the invasiveness of thyroid cancer cells following the activation of the VEGF-C/NRP-2 axis, an NRP-2 function-blocking antibody was used to selectively block the binding of the VEGF family ligands to NRP-2 (29,30). In NRP-2-overexpressing K1 cells, the VEGF-C/NRP-2 axis became defective due to the reduction in ERK and p38 MAPK phosphorylation (Fig.…”