Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer
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Robin M. Hallett1, Adele Girgis-Gabardo1, William D. Gwynne1, Andrew O. Giacomelli1, Jennifer N.P. Bisson1, Jeremy E. Jensen1, Anna Dvorkin-Gheva2, John A. Hassell1,2,3
1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada
2Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
3Department of Biology, McMaster University, Hamilton, ON, L8S 4K1, Canada
John A. Hassell, email: [email protected]
Keywords: breast cancer, tumor-initiating cells, serotonin antagonists, anticancer stem cell drugs
Received: April 01, 2016 Accepted: June 09, 2016 Published: July 15, 2016
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.
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