Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain.
OBJECTIVE
Breast cancer resistance protein (BCRP) is a half adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed on cellular membranes and included in the group of multidrug resistant (MDR)-related proteins. Recently, upregulation of different MDR proteins has been shown in human epilepsy-associated conditions. This study investigated the expression and cellular distribution of BCRP in human control and epileptic brain, including a large number of both neoplastic and nonneoplastic specimens from patients with chronic pharmacoresistant epilepsy.


METHODS
Several epileptogenic pathologies, such as hippocampal sclerosis (HS), focal cortical dysplasia (FCD), dysembryoplastic neuroepithelial tumor, oligodendroglioma astrocytoma, and glioblastoma multiforme were studied by using Western blot and immunocytochemistry.


RESULTS
With Western blot, we could demonstrate the presence of BCRP in both normal and epileptic human brain tissue. In contrast to P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2, BCRP expression levels did not change in tissue from patients with HS, compared with control hippocampus. No BCRP immunoreactivity was observed in glial or neuronal cells, including reactive astrocytes and dysplastic neurons in FCD. BCRP expression was, however, increased in tumor brain tissue. Immunocytochemistry demonstrated that BCRP was exclusively located in blood vessels and was highly expressed at the luminal cell surface and in newly formed tumor capillaries. This localization closely resembles that of P-gp. The higher expression observed in astrocytomas by Western blot analysis was related to the higher vascular density within the tumor tissue.


CONCLUSIONS
These results indicate a constitutive expression of BCRP in human endothelial cells, representing an important barrier against drug access to the brain. In particular, the strong BCRP expression in the microvasculature of epileptogenic brain tumors could critically influence the bioavailability of drugs within the tumor and contribute to pharmacoresistance.
Aronica
Eleonora
E
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. e.aronica@amc.uva.nl
Gorter
Jan A
JA
Redeker
Sandra
S
van Vliet
Erwin A
EA
Ramkema
Marja
M
Scheffer
George L
GL
Scheper
Rik J
RJ
van der Valk
Paul
P
Leenstra
Sieger
S
Baayen
Johannes C
JC
Spliet
Wim G M
WG
Troost
Dirk
D
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis* / Q000378:metabolism; D001254:Astrocytoma / Q000737:chemistry; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism*; D002540:Cerebral Cortex / Q000002:abnormalities / Q000737:chemistry / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000378:metabolism; D004828:Epilepsies, Partial / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008833:Microcirculation; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis*; D009363:Neoplasm Proteins / Q000032:analysis* / Q000378:metabolism; D009837:Oligodendroglioma / Q000737:chemistry / Q000378:metabolism; D012598:Sclerosis; D014018:Tissue Distribution
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human