Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: Correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol

Aberrant cell proliferation and increased invasive and metastatic behavior are hallmarks of the advancement of breast cancer. Numerous studies implica te a role for cholesterol in the mechanisms underlying cell proliferation a nd cancer progression. The peripheral-type benzodiazepine receptor (PBR) is an M-r 18,000 protein primarily localized to the mitochondria, PBR mediate s cholesterol transport across the mitochondrial membranes in steroidogenic cells. A role for PBR in the regulation of tumor cell proliferation has al so been shown. In this study, we examined the expression, characteristics, localization, and function of PBR in a battery of human breast cancer cell lines differing in their invasive and chemotactic potential as well as in s everal human tissue biopsies, Expression of PBR ligand binding and mRNA was dramatically increased in the highly aggressive cell lines, such as MDA-23 1, relative to nonaggressive cell lines, such as MCF-7. PBR was also found to be expressed at high levels in aggressive metastatic human breast tumor biopsies compared with normal breast tissues. Subcellular localization with both antibodies and a fluorescent PBR drug ligand revealed that PBR from t he MDA-231 cell line as well as from aggressive metastatic human breast tum or biopsies sies localized primarily in and around the nucleus. This locali zation is in direct contrast to the largely cytoplasmic localization seen i n MCF-7 cells, normal breast tissue, and to the typical mitochondrial local ization seen in mouse tumor Leydig cells. pharmacological characterization of the receptor and partial nucleotide sequencing of PBR cDNA revealed that the MDA-231 PBR is similar, although not identical, to previously describe d PBR. Addition of high affinity PBR drug ligands to MDA-231 cells increase d the incorporation of bromodeoxyuridine into the cells in a dose-dependent manner, suggesting a role for PER in the regulation of MDA-231 cell prolif eration, Cholesterol uptake into isolated MDA-231 nuclei was found to be 30 % greater than into MCF-7 nuclei. High-affinity PER drug ligands regulated the levels of cholesterol present in MDA-231 nuclei but not in MCF-7, In ad dition, the PER-dependent MDA-231 cell proliferation was found to highly co rrelate (r = -0.99) with the PBR-mediated changes in nuclear membrane chole sterol levels, In conclusion, these data suggest that PER expression, nucle ar localization, and PBR-mediated cholesterol transport into the nucleus ar e involved in human breast cancer cell proliferation and aggressive phenoty pe expression, thus participating in the advancement of the disease.