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.
Highlights
Despite advances in the treatment of primary breast tumors, the outcome of metastatic breast cancer remains dismal
Fluoxetine increases the ability of breast cancer cells to metastasize to the brain To study the effects of fluoxetine on the ability of breast cancer cells to metastasize to the brain, we pretreated Nu/Nu mice with fluoxetine for three weeks prior to the intracardiac injection of 231BR breast cancer cells
We evaluated the direct effect of fluoxetine treatment on extracellular matrix (ECM) composition, in particular on perineuronal nets (PNNs), a major component of the brain ECM that is rich in chondroitin sulfate proteoglycans [28]
Summary
Despite advances in the treatment of primary breast tumors, the outcome of metastatic breast cancer remains dismal. 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. Despite recent advances in the treatment of primary breast cancer tumors, the incidence of fatal metastatic events remains high. The brain provides a unique microenvironment for tumor growth It is a difficult therapeutic target due to the complexity of brain function as well as the reduced ability of therapeutic agents to cross the blood– brain barrier (BBB) [5]. It is becoming increasingly clear that prevention and treatment of metastatic brain tumors requires a better understanding of the mechanisms that determine complex interactions between this unique metastatic milieu and tumor cells [2]
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