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
  • 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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