title: Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer.
abstract: Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hallett
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Adele
authors.initials: A
authors.lastname: Girgis-Gabardo
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Gwynne
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Giacomelli
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Jennifer N P
authors.initials: JN
authors.lastname: Bisson
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Jensen
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Dvorkin-Gheva
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada.|Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Hassell
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D020280:Sertraline / Q000008:administration & dosage / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000077143:Docetaxel; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D043823:Taxoids; C493231:Slc6a4 protein, mouse
keywords: anticancer stem cell drugs; breast cancer; serotonin antagonists; tumor-initiating cells