Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts

William D Gwynne,Robin M Hallett,Anna Dvorkin-Gheva,Craig Aarts,Kay Dias,John A Hassell,Adele Girgis-Gabardo,Anita Bane,Bojana Bojovic

doi:10.18632/oncotarget.16646

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.

Highlights

Breast cancer was the first malignancy of epithelial tumors reported to follow the cancer stem cell (CSC) model [1], which proposes that genomic alterations in tissue-specific cells results in clonal tumor cell populations with stem cell-like properties, including the capacity for self-renewal and differentiation [2]
We have shown that spheres arise from dispersed tumorsphere-derived cells in direct proportion to the number of cells plated into the medium, and that the frequency of sphere-forming cells, which averages 5% of the total tumor cell population in human breast tumor cell line-derived tumorspheres, can be accurately quantified over a range of cell densities [27]
Our data demonstrate that breast tumor cells possess the enzymatic machinery to synthesize 5-HT, which acts by an autocrine or paracrine mechanism in conjunction with other serotonergic pathway components to maintain breast tumor initiating cells (BTIC) activity

Summary

Introduction

Breast cancer was the first malignancy of epithelial tumors reported to follow the cancer stem cell (CSC) model [1], which proposes that genomic alterations in tissue-specific cells results in clonal tumor cell populations with stem cell-like properties, including the capacity for self-renewal and differentiation [2]. Tumors following the CSC model comprise a cellular hierarchy of infrequent BTIC at their apex and an abundant nontumorigenic cell population arising from BTIC at their base. The abundant non-tumorigenic cell population may provide a reservoir of BTIC. These observations have therapeutic implications [6,7,8]. Conventional cytotoxic therapies principally eradicate the abundant non-tumorigenic progeny of BTIC. Tumors regress after cytotoxic www.impactjournals.com/oncotarget therapies, but often recur likely due to therapy-resistant BTIC. To provide durable breast cancer remissions anticancer therapies should eradicate BTIC and their nontumorigenic progeny

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