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Open Access Highly Accessed Research article

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

Yuriy Shapovalov12, Martha Zettel1, Sara C Spielman1, Stacy A Amico-Ruvio1, Emily A Kelly1, Grayson O Sipe1, Ian M Dickerson1, Ania K Majewska1* and Edward B Brown2*

Author Affiliations

1 Department of Neurobiology and Anatomy, University of Rochester School of Medicine & Dentistry, 601 Elmwood Ave, Box 603, Rochester, NY 14642, USA

2 Department of Biomedical Engineering, University of Rochester, Box 270168, Rochester, NY 14627, USA

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BMC Cancer 2014, 14:598  doi:10.1186/1471-2407-14-598

Published: 16 August 2014

Abstract

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.

Keywords:
Breast cancer; Brain metastasis; Fluoxetine; Blood–brain barrier