Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers

Concetta Di Mauro, Roberta Di Rosa, Valentina D'Amato, Paola Ciciola, Alberto Servetto, Roberta Marciano, Roberta Clara Orsini, Luigi Formisano, Sandro De Falco, Valeria Cicatiello, Maurizio Di Bonito, Monica Cantile, Francesca Collina, Angela Chambery, Bianca Maria Veneziani, Sabino De Placido, Roberto Bianco

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated.Methods: Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice.Results: Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation.Conclusions: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.

Original languageEnglish
Pages (from-to)1425-1435
Number of pages11
JournalBritish Journal of Cancer
Volume116
Issue number11
DOIs
Publication statusPublished - May 23 2017

Keywords

  • Angiogenesis
  • GLI1
  • Hedgehog
  • NVP-LDE225
  • TNBC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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