title: Anti-cell growth and anti-cancer stem cell activities of the non-canonical hedgehog inhibitor GANT61 in triple-negative breast cancer cells.
abstract: BACKGROUND
  Triple-negative breast cancer (TNBC) exhibits biologically aggressive behavior and has a poor prognosis. Novel molecular targeting agents are needed to control TNBC. Recent studies revealed that the non-canonical hedgehog (Hh) signaling pathway plays important roles in the regulation of cancer stem cells (CSCs) in breast cancer. Therefore, the anti-cell growth and anti-CSC effects of the non-canonical Hh inhibitor GANT61 were investigated in TNBC cells.
  
  
  METHODS
  The effects of GANT61 on cell growth, cell cycle progression, apoptosis, and the proportion of CSCs were investigated in three TNBC cell lines. Four ER-positive breast cancer cell lines were also used for comparisons. The expression levels of effector molecules in the Hh pathway: glioma-associated oncogene (GLI) 1 and GLI2, were measured. The combined effects of GANT61 and paclitaxel on anti-cell growth and anti-CSC activities were also investigated.
  
  
  RESULTS
  Basal expression levels of GLI1 and GLI2 were significantly higher in TNBC cells than in ER-positive breast cancer cells. GANT61 dose-dependently decreased cell growth in association with G1-S cell cycle retardation and increased apoptosis. GANT61 significantly decreased the CSC proportion in all TNBC cell lines. Paclitaxel decreased cell growth, but not the CSC proportion. Combined treatments of GANT61 and paclitaxel more than additively enhanced anti-cell growth and/or anti-CSC activities.
  
  
  CONCLUSIONS
  The non-canonical Hh inhibitor GANT61 decreased not only cell growth, but also the CSC population in TNBC cells. GANT61 enhanced the anti-cell growth activity of paclitaxel in these cells. These results suggest for the first time that GANT61 has potential as a therapeutic agent in the treatment of patients with TNBC.
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Koike
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Saitoh
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Tetsumasa
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Pathology 2, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanomata
authors.affiliation: Department of Pathology 2, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. kure@med.kawasaki-m.ac.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kurebayashi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005455:Fluorescent Antibody Technique; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C551027:GANT 61; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D011725:Pyridines; D011743:Pyrimidines; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D017239:Paclitaxel
keywords: Cancer stem cells; GANT61; Hedgehog pathway; Paclitaxel; Triple-negative breast cancer