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Published on: February 4, 2021
Fluoxetine modulates breast cancer metastasis to the brain in a murine model
Yuriy Shapovalov, Martha Zettel, Sara C Spielman
1Department of Neurobiology and Anatomy, University of Rochester School of Medicine & Dentistry, 601 Elmwood Ave, Box 603, Rochester, NY 14642, USA. Ania_Majewska@urmc.rochester.edu.
Background:
Despite 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.
Methods:
We studied the effect of fluoxetine, an SSRI, on the development of brain metastatic breast cancer using MDA-MB-231BR cells in a mouse model.
Results:
The 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.
Conclusion:
Our 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.
Insights
Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine may worsen brain metastases in breast cancer patients. This study found fluoxetine increased brain metastases by affecting the blood-brain barrier and immune cells in the brain.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Metastatic breast cancer, particularly brain metastases, has a poor prognosis.
- The brain's sanctuary status limits chemotherapy effectiveness.
- Neuroactive drugs, including antidepressants, are common in breast cancer patients.
Purpose of the Study:
- To investigate the impact of selective serotonin reuptake inhibitors (SSRIs) on brain metastasis development.
- To explore the potential influence of commonly prescribed neuroactive medications on brain metastasis pathogenesis.
Main Methods:
- Utilized a mouse model of brain metastatic breast cancer.
- Administered fluoxetine, a selective serotonin reuptake inhibitor (SSRI), to assess its effects.
- Examined changes in blood-brain barrier permeability, neuroinflammation, and glial activation.
Main Results:
- Fluoxetine treatment significantly increased the number of brain metastases.
- Observed elevated blood-brain barrier permeability and pro-inflammatory changes in the brain.
- Detected glial activation, suggesting a role for brain-resident immune cells.
Conclusions:
- Neuroactive substances can influence the pathogenesis of brain metastatic disease.
- Findings suggest a potential mechanism involving immune cells and glia in promoting brain metastasis.
- Opens avenues for developing novel anti-metastasis therapies targeting drug-tumor-brain interactions.
