title: Anti-cancer stem cell activity of a hedgehog inhibitor GANT61 in estrogen receptor-positive breast cancer cells.
abstract: Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)-positive breast cancer cells. It has been suggested that the non-canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER-positive breast cancer cells. We studied anti-CSC activity of a non-canonical Hh inhibitor GANT61 in ER-positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER-positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti-cell growth and anti-CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER-positive cell lines. E2 increased the expression levels of glioma-associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1-S cell cycle retardation and increased apoptosis. GANT61 decreased the E2-induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2-induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti-cell growth and/or anti-CSC activities in some ER-positive cell lines. In conclusion, the non-canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER-positive breast cancer cells. GANT61 enhanced anti-cell growth and/or anti-CSC activities of antiestrogens in ER-positive cell lines.
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Junichi
authors.identifier: http://orcid.org/0000-0003-0356-842X
authors.initials: J
authors.lastname: Kurebayashi
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Koike
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Saitoh
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Tetsumasa
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Pathology 2, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanomata
authors.affiliation: Department of Pathology 2, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; C551027:GANT 61; D053823:Hedgehog Proteins; D011725:Pyridines; D011743:Pyrimidines; D011960:Receptors, Estrogen; D004958:Estradiol
keywords: Antiestrogen; GANT61; breast cancer stem cells; estrogen; hedgehog signaling pathway