The Role of Serotonin in Breast Cancer Stem Cells
Abstract
1. Introduction
1.1. Breast Cancer Clinical and Molecular Subtypes
1.2. Breast Cancer Stem Cells
1.3. Epithelial to Mesenchymal Transition and BTIC, Therapeutic Implications
2. Discovery of BTIC Targeting Small Molecules
2.1. Identification of an Abundant Source of BTIC
2.2. Phenotypic Screen in Mouse BTIC-Enriched Tumor Cells Identifies Neurotransmitter Antagonists
2.3. 5-HT and Proteins Required for Its Synthesis, Transport, and Activity via 5-HTRs Are Expressed in Mouse Mammary Tumor Cells
2.4. 5-HT Is Synthesized by Mouse Mammary Tumor Cells, Which Express TPH1 and SERT
2.5. Serotonergic Antagonists Target BTIC from a Mouse Model of HER2-Overexpressing Breast Cancer
2.6. Serotonergic Antagonist Function by an Irreversible Mechanism to Reduce BTIC Frequency
2.7. Serotonergic Antagonists Synergize with Chemotherapy to Shrink Mouse Mammary Tumors
2.8. Sertraline in Combination with Docetaxel Reduces Tumor Cell Proliferation and Induces Programmed Cell Death in Mammary Tumor Allografts
2.9. Summary
3. 5-HT and Human Cancers
3.1. Human Breast Tumors, Patient-Derived Xenografts and Breast Tumor Cell Lines Synthesize 5-HT and Express Proteins Required for Its Biosynthesis and Activity
3.2. Selective Antagonists of Multiple 5-HT System Pathway Components Reduce BTIC Frequency in Human Breast Tumor Cell Lines and Synergize with Chemotherapy to Shrink Breast Tumor Xenografts
3.3. Functional Evidence for 5-HTRs in Human Breast Cancer and Other Cancers
4. Monoamine Oxidase A (MAO-A)
5. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Abbreviation | Definition |
5-HT | 5-Hydroxytryptamine |
WB | Western blot |
5-HTRs | 5-HT receptors |
TNBC | Triple-negative breast cancer |
ER | Estrogen receptor |
PR | Progesterone receptor |
BTICs | Breast tumor-initiating cell |
EMT | Epithelial to mesenchymal transition |
GPCRs | G-protein coupled receptors |
SERT | Serotonin reuptake transporter |
5-HT | 5-hydroxytryptamine |
SSRI | Selective serotonin reuptake inhibitors |
TPH1 | Tryptophan hydroxylase 1 |
MAO | Monoamine oxidase |
MESC | Mammary epithelial stem cells |
TIC | Tumor-initiating cells |
TUNEL | Terminal deoxynucleotidyl transferase dUTP nick end labeling |
IHC | Immunohistochemistry |
IF | Immunofluorescence |
RTK | Receptor tyrosine kinase |
5-CT | 5-carboxamidotryptamine |
ERKs | Extracellular regulated kinases |
cAMP | Cyclic adenosine monophosphate |
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Protein | Sample Type | Detection Method | Reference | |
---|---|---|---|---|
SERT | MMTV-Her2/Neu tumorspheres and tumors | IF | [22,43,56] | |
Patient-derived breast tumors xenografts | IHC | |||
Human breast tumor cell lines, tumorspheres and xenografts | WB, IF, RT-PCR | |||
TPH1 | MMTV-Her2/Neu tumorspheres and tumors | IF | [22,43,55,56] | |
Human breast tumor cell lines, tumorspheres and xenografts | IF | |||
5-HT | MMTV-Her2/Neu tumorspheres and tumors | IF | [22,43] | |
Human breast tumor cell line tumorspheres and xenografts | IF | |||
MAO-A | Human breast tumor cell lines and tumorspheres | NanoString, WB | [57,58,59] | |
Chemically induced rat mammary tumors | Enzymatic | |||
5-HTR | 1A 1B 2A 2B 4 5A 7 | Human breast tumor cell lines | DNA microarray, RT-PCR, IF, WB | [52,53,54,55,56] |
Molecule | FDA-Approved | Target | Sample Type | Species | Observed Effects |
---|---|---|---|---|---|
LP533401 | No | TPH1 | MMTV-Her2/Neu | Mouse | Inhibits tumorsphere formation [22,43] |
Breast tumor cell lines | Human | ||||
Sertraline | Yes | SERT | MMTV-Her2/Neu | Mouse | Inhibits tumorsphere formation [22] |
Targets tumor-initiating cells [22] | |||||
Induces tumor regression in combination with docetaxel [22] | |||||
Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] | |||
Targets tumor initiating cells [43] | |||||
Paroxetine | Yes | SERT | MMTV-Her2/Neu | Mouse | Inhibits tumorsphere formation [22,43] |
Breast tumor cell lines | Human | ||||
Fluoxetine | Yes | SERT | MMTV-Her2/Neu | Mouse | Inhibits tumorsphere formation [22,43] |
Breast tumor cell lines | Human | ||||
Vortioxetine | Yes | SERT | Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] |
Vilazodone | Yes | SERT, 5-HTR1A | Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] |
Induces tumor regression in combination with docetaxel [43] | |||||
SB-224289 | No | 5-HTR1B | MMTV-Her2/Neu | Mouse | Inhibits tumorsphere formation [22,43] |
Breast tumor cell lines | Human | ||||
GR-127935 | No | 5-HTR1D | Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] |
4F-4PP | No | 5-HTR2A | Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] |
SB-204741 | No | 5-HTR2B | Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] |
SB-242084 | No | 5-HTR2C | Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] |
SB-699551 | No | 5-HTR5A | MMTV-Her2/Neu | Mouse | Inhibits tumorsphere formation [22,61] |
Breast tumor cell lines Patient-dervied breast tumor xenografts | Human | Inhibits tumorsphere formation [43] | |||
Targets tumor-initiating cells [61] | |||||
Induces tumor regression in combination with docetaxel [61] | |||||
MS-245 | No | 5-HTR6 | MMTV-Her2/Neu | Mouse | Inhibits tumorsphere formation [22] |
NPS ALX Compound 4a | No | 5-HTR6 | Breast tumor cell lines | Human | Inhibits tumorsphere formation [43] |
Tetrindole | No | MAOA | Breast tumor cell lines | Human | Inhibits tumorsphere formation [57] |
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Gwynne, W.D.; Shakeel, M.S.; Girgis-Gabardo, A.; Hassell, J.A. The Role of Serotonin in Breast Cancer Stem Cells. Molecules 2021, 26, 3171. https://doi.org/10.3390/molecules26113171
Gwynne WD, Shakeel MS, Girgis-Gabardo A, Hassell JA. The Role of Serotonin in Breast Cancer Stem Cells. Molecules. 2021; 26(11):3171. https://doi.org/10.3390/molecules26113171
Chicago/Turabian StyleGwynne, William D., Mirza S. Shakeel, Adele Girgis-Gabardo, and John A. Hassell. 2021. "The Role of Serotonin in Breast Cancer Stem Cells" Molecules 26, no. 11: 3171. https://doi.org/10.3390/molecules26113171
APA StyleGwynne, W. D., Shakeel, M. S., Girgis-Gabardo, A., & Hassell, J. A. (2021). The Role of Serotonin in Breast Cancer Stem Cells. Molecules, 26(11), 3171. https://doi.org/10.3390/molecules26113171