title: Fluoxetine modulates breast cancer metastasis to the brain in a murine model.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Shapovalov
authors.forename: Martha
authors.initials: M
authors.lastname: Zettel
authors.forename: Sara C
authors.initials: SC
authors.lastname: Spielman
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Amico-Ruvio
authors.forename: Emily A
authors.initials: EA
authors.lastname: Kelly
authors.forename: Grayson O
authors.initials: GO
authors.lastname: Sipe
authors.forename: Ian M
authors.initials: IM
authors.lastname: Dickerson
authors.affiliation: Department 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.
authors.forename: Ania K
authors.initials: AK
authors.lastname: Majewska
authors.forename: Edward B
authors.initials: EB
authors.lastname: Brown
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D001932:Brain Neoplasms / Q000097:blood / Q000556:secondary*; D001943:Breast Neoplasms / Q000097:blood / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D049229:Dendritic Spines / Q000473:pathology; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D005473:Fluoxetine