Abstract
Several recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.
Highlights
The five dopamine receptors (DRD1–5) are G-protein-coupled receptors (GPCRs) that mediate responses to the catecholamine dopamine[1,2]
We show that drugs that primarily block dopamine receptor 2 (DRD2) mRNA and protein can be detected in all breast cancer cell lines tested, suggesting DRD2 expression alone cannot be used to predict whether the self-renewal of a cell line will be sensitive to thioridazine
We previously showed that 1 μM thioridazine inhibits self-renewal in some triple-negative breast cancer cell lines through DRD2 inhibition[16]
Summary
The five dopamine receptors (DRD1–5) are G-protein-coupled receptors (GPCRs) that mediate responses to the catecholamine dopamine[1,2]. 30 years ago, thioridazine and pimozide, antipsychotic drugs that primarily block dopamine receptor 2 (DRD2), were shown to inhibit the proliferation of breast cancer cell lines[7,8]. Our study showed that thioridazine inhibits self-renewal of certain triple-negative breast cancer cell lines via DRD2 inhibition[16]. We had previously shown that 1–2 μM thioridazine can inhibit the tumorsphere formation of some triple-negative breast cancer cell lines, but not others[16], and in this study we sought to address whether cells from some breast cancer subtypes are more sensitive than others. Critical outstanding questions surrounding the potential use of DRD2-targeting antipsychotics in cancer are the identification of tumor types in which these drugs will be most effective and determining how tumor-expressed dopamine receptors are activated. We report the detection of dopamine in human and mouse triple-negative breast tumor samples, showing that tumor-associated dopamine may be functional in human tumors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
