title: Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts.
abstract: Breast tumors comprise an infrequent tumor cell population, termed breast tumor initiating cells (BTIC), which sustain tumor growth, seed metastases and resist cytotoxic therapies. Hence therapies are needed to target BTIC to provide more durable breast cancer remissions than are currently achieved. We previously reported that serotonergic system antagonists abrogated the activity of mouse BTIC resident in the mammary tumors of a HER2-overexpressing model of breast cancer. Here we report that antagonists of serotonin (5-hydroxytryptamine; 5-HT) biosynthesis and activity, including US Federal Food and Drug Administration (FDA)-approved antidepressants, targeted BTIC resident in numerous breast tumor cell lines regardless of their clinical or molecular subtype. Notably, inhibitors of tryptophan hydroxylase 1 (TPH1), required for 5-HT biosynthesis in select non-neuronal cells, the serotonin reuptake transporter (SERT) and several 5-HT receptors compromised BTIC activity as assessed by functional sphere-forming assays. Consistent with these findings, human breast tumor cells express TPH1, 5-HT and SERT independent of their molecular or clinical subtype. Exposure of breast tumor cells ex vivo to sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), reduced BTIC frequency as determined by transplanting drug-treated tumor cells into immune-compromised mice. Moreover, another SSRI (vilazodone; Viibryd) synergized with chemotherapy to shrink breast tumor xenografts in immune-compromised mice by inhibiting tumor cell proliferation and inducing their apoptosis. Collectively our data suggest that antidepressants in combination with cytotoxic anticancer therapies may be an appropriate treatment regimen for testing in clinical trials.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Gwynne
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Canada.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hallett
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Canada.
authors.forename: Adele
authors.initials: A
authors.lastname: Girgis-Gabardo
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Canada.
authors.forename: Bojana
authors.initials: B
authors.lastname: Bojovic
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Dvorkin-Gheva
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: Aarts
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Canada.
authors.forename: Kay
authors.initials: K
authors.lastname: Dias
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Canada.
authors.forename: Anita
authors.initials: A
authors.lastname: Bane
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Hassell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase
keywords: antidepressants; breast cancer stem cells; cytotoxic chemotherapy; serotonin antagonists; tumor-initiating cells