2. Academic Validation
  3. Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells

Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells

  • Cancer Lett. 2017 Dec 28;411:136-149. doi: 10.1016/j.canlet.2017.09.033.
Helen O Oladapo 1,  Michael Tarpley 1,  Scott J Sauer 2,  Kezia A Addo 1,  Shalonda M Ingram 1,  Dillon Strepay 3,  Ben K Ehe 1,  Lhoucine Chdid 1,  Michael Trinkler 4,  Jose R Roques 4,  David B Darr 5,  Jodie M Fleming 6,  Gayathri R Devi 7,  Kevin P Williams 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC, 27707, USA.
  • 2 Department of Surgery, Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, 27710, USA.
  • 3 Department of Biological and Biomedical Sciences, North Carolina Central University, Durham, NC, 27707, USA.
  • 4 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 5 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 6 Department of Biological and Biomedical Sciences, North Carolina Central University, Durham, NC, 27707, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 7 Department of Surgery, Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, 27710, USA; Duke Cancer Institute, Duke University, Durham, NC 27710, USA. Electronic address: [email protected].
  • 8 Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC, 27707, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Duke Cancer Institute, Duke University, Durham, NC 27710, USA. Electronic address: [email protected].
PMID: 28965853 DOI: 10.1016/j.canlet.2017.09.033
Abstract

Activation of the Hedgehog (Hh) pathway effector GLI1 is linked to tumorigenesis and invasiveness in a number of cancers, with targeting of GLI1 by small molecule antagonists shown to be effective. We profiled a collection of Gli antagonists possessing distinct mechanisms of action for efficacy in phenotypic models of inflammatory and non-inflammatory breast Cancer (IBC and non-IBC) that we showed expressed varying levels of Hh pathway mediators. Compounds GANT61, HPI-1, and JK184 decreased cell proliferation, inhibited GLI1 mRNA expression and decreased the number of colonies formed in TN-IBC (SUM149) and TNBC (MDA-MB-231 and SUM159) cell lines. In addition, GANT61 and JK184 significantly down-regulated GLI1 targets that regulate cell cycle (cyclin D and E) and Apoptosis (Bcl2). GANT61 reduced SUM149 spheroid growth and emboli formation, and in orthotopic SUM149 tumor models significantly decreased tumor growth. We successfully utilized phenotypic profiling to identify a subset of GLI1 antagonists that were prioritized for testing in in vivo models. Our results indicated that GLI1 activation in TN-IBC as in TNBC, plays a vital role in promoting cell proliferation, motility, tumor growth, and formation of tumor emboli.

Keywords

GANT61; GLI1; Hedgehog; IBC; JK184; SUM149.

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