title: Both bulk and cancer stem cell subpopulations in triple-negative breast cancer are susceptible to Wnt, HDAC, and ERα coinhibition.
abstract: Development of targeted therapies for triple-negative breast cancer (TNBC, a more aggressive subtype) is an unmet medical need. We analyzed data from 887 patients with invasive breast cancer and observed that increased Wnt and histone deacetylase (HDAC) activities are associated with estrogen receptor 1 (ESR1) and progesterone receptor (PGR) repression, poor survival, and increased relapse. The inverse correlation between Wnt signaling and repression of ESR1 and PGR expression was found to be magnified in cancer stem cell (CSC) subpopulations in TNBC cell lines. Cosuppression of Wnt, HDAC, and ESR1 using clinically relevant low-dose inhibitors effectively repressed both bulk and CSC subpopulations and converted CSCs to non-CSCs in TNBC cells without affecting MCF-10A mammary epithelial cells.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sulaiman
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.
authors.forename: Brandon
authors.initials: B
authors.lastname: Sulaiman
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.
authors.forename: Lara
authors.initials: L
authors.lastname: Khouri
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: McGarry
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Nessim
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada.
authors.forename: Angel
authors.initials: A
authors.lastname: Arnaout
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.|Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada Sir Frederick G. Banting Research Centre, Ottawa, Canada.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.|Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Addison
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.|Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Canada.|Regenerative Medicine Program, Ottawa Hospital Research Institute, Canada.|Ottawa Institute of Systems Biology, University of Ottawa, Canada.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D011980:Receptors, Progesterone / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051927:CD24 Antigen; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D013629:Tamoxifen; D014635:Valproic Acid; D051153:Wnt Proteins; D051176:beta Catenin; C497889:CD24 protein, human; C497483:CD44 protein, human; C495270:CTNNB1 protein, human; C506487:ESR1 protein, human; C508053:ERBB2 protein, human
keywords: 
  HDAC
  ; 
  TNBC
  ; ESR1; Wnt; cancer stem cell