title: Histone Deacetylase Inhibitor Entinostat Inhibits Tumor-Initiating Cells in Triple-Negative Breast Cancer Cells.
abstract: Mortality following breast cancer diagnosis is mainly due to the development of distant metastasis. To escape from the primary site, tumor cells undergo the epithelial-to-mesenchymal transition (EMT), which helps them acquire a more motile and invasive phenotype. In our previous study, we showed that class I selective HDAC inhibitor entinostat reverses the EMT phenotype through reversal of epigenetic repression of E-cadherin. Recent evidence suggests that a subset of cells within a breast tumor may drive the metastatic outgrowth following escape from the primary site. These cells, termed tumor-initiating cells (TIC), represent a great threat to overall prognosis. They are critical in terms of drug resistance and tumor initiation at metastatic sites. Acquisition of EMT traits has also been shown to impart TIC phenotype to the cells, making EMT a "dual-threat" for prognosis. In the current study, we show that entinostat treatment can reduce the percentage of TIC cells from triple-negative breast cancer (TNBC) cells. Entinostat treatment was able to reduce the CD44(high)/CD24(low) cell population, ALDH-1 activity, as well as protein and mRNA expression of known TIC markers such as Bmi-1, Nanog, and Oct-4. Next, we inoculated MDA-MB-231 cells transfected with firefly luciferase (231/Luc) in mammary fat pad of NSG mice. The mice were then treated with entinostat (2.5 mg/kg/d), and tumor development and formation of metastasis were assessed by bioluminescence imaging. Treatment with entinostat significantly reduced tumor formation at the primary site as well as lung metastasis. As such, entinostat may help prevent development of distant metastasis.
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland.
authors.forename: Amanda
authors.initials: A
authors.lastname: Schech
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland. Department of Biology, Loyola University Maryland, Baltimore, Maryland.
authors.forename: Armina
authors.initials: A
authors.lastname: Kazi
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland.
authors.forename: Preeti
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland. gsabnis@som.umaryland.edu.
authors.forename: Gauri
authors.initials: G
authors.lastname: Sabnis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015415:Biomarkers; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D016130:Immunophenotyping; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D051927:CD24 Antigen; D056572:Histone Deacetylase Inhibitors; D018960:Hyaluronan Receptors; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D011725:Pyridines; C118739:entinostat