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Cancer Lett. 2017 Dec 28;411:136-149. doi: 10.1016/j.canlet.2017.09.033. Epub 2017 Sep 28.

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

Author information

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: gayathri.devi@duke.edu.
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: kpwilliams@nccu.edu.

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

PMID:
28965853
PMCID:
PMC5720365
DOI:
10.1016/j.canlet.2017.09.033
[Indexed for MEDLINE]
Free PMC Article

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