Fluoxetine modulates breast cancer metastasis to the brain in a murine model

Abstract

BackgroundDespite advances in the treatment of primary breast tumors, the outcome of metastatic breast cancer remains dismal. Brain metastases present a particularly difficult therapeutic target due to the “sanctuary” status of the brain, with resulting inability of most chemotherapeutic agents to effectively eliminate cancer cells in the brain parenchyma. A large number of breast cancer patients receive various neuroactive drugs to combat complications of systemic anti-tumor therapies and to treat concomitant diseases. One of the most prescribed groups of neuroactive medications is anti-depressants, in particular selective serotonin reuptake inhibitors (SSRIs). Since SSRIs have profound effects on the brain, it is possible that their use in breast cancer patients could affect the development of brain metastases. This would provide important insight into the mechanisms underlying brain metastasis. Surprisingly, this possibility has been poorly explored.MethodsWe studied the effect of fluoxetine, an SSRI, on the development of brain metastatic breast cancer using MDA-MB-231BR cells in a mouse model.ResultsThe data demonstrate that fluoxetine treatment increases the number of brain metastases, an effect accompanied by elevated permeability of the blood–brain barrier, pro-inflammatory changes in the brain, and glial activation. This suggests a possible role of brain-resident immune cells and glia in promoting increased development of brain metastases.ConclusionOur results offer experimental evidence that neuroactive substances may influence the pathogenesis of brain metastatic disease. This provides a starting point for further investigations into possible mechanisms of interaction between various neuroactive drugs, tumor cells, and the brain microenvironment, which may lead to the discovery of compounds that inhibit metastasis to the brain.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-598) contains supplementary material, which is available to authorized users.

Antidepressant use and risk of central nervous system metastasis

“…In contrast to these findings, mRNA expression of TNF-α, IL-1α, IL-1β, and intercellular adhesion molecule-1 (ICAM-1) was increased in vivo using polymerase chain reaction (PCR) analysis and may affect the BBB permeability [14]. However, a double-blind study in human subjects found no association between cytokine levels IL-6, IL-8, IL-10, TNF-α, and IL-1ra and escitalopram use [301].…”

“…Also suspected as a risk factor for brain metastasis by Shapovalov et al [14] is antidepressant use.…”

“…Shapovalov et al found an association between pretreatment with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), and an increase in brain metastasis from breast cancer in mice [14]. Since cancer patients are more likely to have a diagnosis of depression and, consequently, be prescribed antidepressant medication [284][285][286], it is important to determine the effects of antidepressants on disease progression to the brain.…”

“…Additionally, the majority of studies finding an anti-inflammatory effect failed to examine the baseline inflammatory state and instead examined inflammation due to lipopolysaccharide (LPS) injection or CNS disease [14,302,303]. More research should be conducted to confirm the differences in the in vitro and in vivo setting.…”

“…To the best of our knowledge, one study analyzed the risk of CNS metastasis associated with antidepressant use [14]. In mice injected with the MDA-MB213BR-GFP breast cancer cell line, Shapovalov et al [14] reported a 52% increase in total number of brain metastases in those mice that received fluoxetine in comparison to controls.…”