This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hardwick, M. Articles by Papadopoulos, V. Search for Related Content PubMed PubMed Citation Articles by Hardwick, M. Articles by Papadopoulos, V.

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 Cholesterol¹

Departments of Cell Biology [M. H., D. F., M. C., H. L., B. V., V. P.] and Pharmacology [V. P.], and the Lombardi Cancer Center [M. C., V. P.], Georgetown University Medical Center, Washington, DC 20007

Aberrant cell proliferation and increased invasive and metastatic behavior are hallmarks of the advancement of breast cancer. Numerous studies implicate a role for cholesterol in the mechanisms underlying cell proliferation and cancer progression. The peripheral-type benzodiazepine receptor (PBR) is an M_r 18,000 protein primarily localized to the mitochondria. PBR mediates cholesterol transport across the mitochondrial membranes in steroidogenic cells. A role for PBR in the regulation of tumor cell proliferation has also 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 several human tissue biopsies. Expression of PBR ligand binding and mRNA was dramatically increased in the highly aggressive cell lines, such as MDA-231, 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 the MDA-231 cell line as well as from aggressive metastatic human breast tumor biopsies localized primarily in and around the nucleus. This localization is in direct contrast to the largely cytoplasmic localization seen in MCF-7 cells, normal breast tissue, and to the typical mitochondrial localization 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 described PBR. Addition of high affinity PBR drug ligands to MDA-231 cells increased the incorporation of bromodeoxyuridine into the cells in a dose-dependent manner, suggesting a role for PBR in the regulation of MDA-231 cell proliferation. Cholesterol uptake into isolated MDA-231 nuclei was found to be 30% greater than into MCF-7 nuclei. High-affinity PBR drug ligands regulated the levels of cholesterol present in MDA-231 nuclei but not in MCF-7. In addition, the PBR-dependent MDA-231 cell proliferation was found to highly correlate (r = -0.99) with the PBR-mediated changes in nuclear membrane cholesterol levels. In conclusion, these data suggest that PBR expression, nuclear localization, and PBR-mediated cholesterol transport into the nucleus are involved in human breast cancer cell proliferation and aggressive phenotype expression, thus participating in the advancement of the disease.

This article has been cited by other articles:

				B. Costa, S. Pini, P. Gabelloni, E. Da Pozzo, M. Abelli, L. Lari, M. Preve, A. Lucacchini, G. B. Cassano, and C. Martini The Spontaneous Ala147Thr Amino Acid Substitution within the Translocator Protein Influences Pregnenolone Production in Lymphomonocytes of Healthy Individuals Endocrinology, December 1, 2009; 150(12): 5438 - 5445. [Abstract] [Full Text] [PDF]

				J. Fan, M. B. Rone, and V. Papadopoulos Translocator Protein 2 Is Involved in Cholesterol Redistribution during Erythropoiesis J. Biol. Chem., October 30, 2009; 284(44): 30484 - 30497. [Abstract] [Full Text] [PDF]

				A. Fafalios, A. Akhavan, A. V. Parwani, R. R. Bies, K. J. McHugh, and B. R. Pflug Translocator Protein Blockade Reduces Prostate Tumor Growth Clin. Cancer Res., October 1, 2009; 15(19): 6177 - 6184. [Abstract] [Full Text] [PDF]

				N. G. Deane, H. C. Manning, A. C. Foutch, M. K. Washington, B. A. Aronow, D. J. Bornhop, and R. J. Coffey Targeted Imaging of Colonic Tumors in Smad3-/- Mice Discriminates Cancer and Inflammation Mol. Cancer Res., April 1, 2007; 5(4): 341 - 349. [Abstract] [Full Text] [PDF]

				M.-K. Chen and T. R. Guilarte Imaging the Peripheral Benzodiazepine Receptor Response in Central Nervous System Demyelination and Remyelination Toxicol. Sci., June 1, 2006; 91(2): 532 - 539. [Abstract] [Full Text] [PDF]

				B. Costa, A. Salvetti, L. Rossi, F. Spinetti, A. Lena, B. Chelli, M. Rechichi, E. Da Pozzo, V. Gremigni, and C. Martini Peripheral Benzodiazepine Receptor: Characterization in Human T-Lymphoma Jurkat Cells Mol. Pharmacol., January 1, 2006; 69(1): 37 - 44. [Abstract] [Full Text] [PDF]

				R. B. Walter, J. L. Pirga, M. R. Cronk, S. Mayer, F. R. Appelbaum, and D. E. Banker PK11195, a peripheral benzodiazepine receptor (pBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a pBR-independent, direct transporter-modulating mechanism Blood, November 15, 2005; 106(10): 3584 - 3593. [Abstract] [Full Text] [PDF]

				P. Lindemann, A. Koch, B. Degenhardt, G. Hause, B. Grimm, and V. Papadopoulos A Novel Arabidopsis thaliana Protein is a Functional Peripheral-Type Benzodiazepine Receptor Plant Cell Physiol., June 15, 2004; 45(6): 723 - 733. [Abstract] [Full Text] [PDF]

				A. Mitchell, C. R. Dass, L.-Q. Sun, and L. M. Khachigian Inhibition of human breast carcinoma proliferation, migration, chemoinvasion and solid tumour growth by DNAzymes targeting the zinc finger transcription factor EGR-1 Nucleic Acids Res., June 4, 2004; 32(10): 3065 - 3069. [Abstract] [Full Text] [PDF]

				S. L. Ettinger, R. Sobel, T. G. Whitmore, M. Akbari, D. R. Bradley, M. E. Gleave, and C. C. Nelson Dysregulation of Sterol Response Element-Binding Proteins and Downstream Effectors in Prostate Cancer during Progression to Androgen Independence Cancer Res., March 15, 2004; 64(6): 2212 - 2221. [Abstract] [Full Text] [PDF]

				S. Galiegue, P. Casellas, A. Kramar, N. Tinel, and J. Simony-Lafontaine Immunohistochemical Assessment of the Peripheral Benzodiazepine Receptor in Breast Cancer and Its Relationship with Survival Clin. Cancer Res., March 15, 2004; 10(6): 2058 - 2064. [Abstract] [Full Text] [PDF]

				C. Giatzakis and V. Papadopoulos Differential Utilization of the Promoter of Peripheral-Type Benzodiazepine Receptor by Steroidogenic Versus Nonsteroidogenic Cell Lines and the Role of Sp1 and Sp3 in the Regulation of Basal Activity Endocrinology, March 1, 2004; 145(3): 1113 - 1123. [Abstract] [Full Text] [PDF]

				E. Bribes, D. Carriere, C. Goubet, S. Galiegue, P. Casellas, and J. Simony-Lafontaine Immunohistochemical Assessment of the Peripheral Benzodiazepine Receptor in Human Tissues J. Histochem. Cytochem., January 1, 2004; 52(1): 19 - 28. [Abstract] [Full Text] [PDF]

				T. Sugawara, H. Shimizu, N. Hoshi, A. Nakajima, and S. Fujimoto Steroidogenic Acute Regulatory Protein-binding Protein Cloned by a Yeast Two-hybrid System J. Biol. Chem., October 24, 2003; 278(43): 42487 - 42494. [Abstract] [Full Text] [PDF]

				A. Boitano, J. A. Ellman, G. D. Glick, and A. W. Opipari Jr. The Proapoptotic Benzodiazepine Bz-423 Affects the Growth and Survival of Malignant B Cells Cancer Res., October 15, 2003; 63(20): 6870 - 6876. [Abstract] [Full Text] [PDF]

				M. Gazouli, Z. Han, and V. Papadopoulos Identification of a Peptide Antagonist to the Peripheral-Type Benzodiazepine Receptor That Inhibits Hormone-Stimulated Leydig Cell Steroid Formation J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 627 - 632. [Abstract] [Full Text] [PDF]

				L. Shan, M. He, M. Yu, C. Qiu, N. H. Lee, E. T. Liu, and E. G. Snyderwine cDNA microarray profiling of rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 7,12-dimethylbenz[a]anthracene Carcinogenesis, October 1, 2002; 23(10): 1561 - 1568. [Abstract] [Full Text] [PDF]

				J. Chen, A. Freeman, J. Liu, Q. Dai, and R.-m. Lee The Apoptotic Effect of HA14-1, a Bcl-2-interacting Small Molecular Compound, Requires Bax Translocation and Is Enhanced by PK11195 Mol. Cancer Ther., October 1, 2002; 1(12): 981 - 987. [Abstract] [Full Text] [PDF]

				K. Maaser, P. Grabowski, A. P. Sutter, M. Hopfner, H.-D. Foss, H. Stein, G. Berger, M. Gavish, M. Zeitz, and H. Scherubl Overexpression of the Peripheral Benzodiazepine Receptor Is a Relevant Prognostic Factor in Stage III Colorectal Cancer Clin. Cancer Res., October 1, 2002; 8(10): 3205 - 3209. [Abstract] [Full Text] [PDF]

				M. Gazouli, Z.-X. Yao, N. Boujrad, J. C. Corton, M. Culty, and V. Papadopoulos Effect of Peroxisome Proliferators on Leydig Cell Peripheral-Type Benzodiazepine Receptor Gene Expression, Hormone-Stimulated Cholesterol Transport, and Steroidogenesis: Role of the Peroxisome Proliferator-Activator Receptor {alpha} Endocrinology, July 1, 2002; 143(7): 2571 - 2583. [Abstract] [Full Text] [PDF]

				R. B. Banati, J. Newcombe, R. N. Gunn, A. Cagnin, F. Turkheimer, F. Heppner, G. Price, F. Wegner, G. Giovannoni, D. H. Miller, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: Quantitative in vivo imaging of microglia as a measure of disease activity Brain, November 1, 2000; 123(11): 2321 - 2337. [Abstract] [Full Text] [PDF]

				W. Xia, S. Spector, L. Hardy, S. Zhao, A. Saluk, L. Alemane, and N. L. Spector Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine PNAS, June 20, 2000; 97(13): 7494 - 7499. [Abstract] [Full Text] [PDF]

				M. Gavish, I. Bachman, R. Shoukrun, Y. Katz, L. Veenman, G. Weisinger, and A. Weizman Enigma of the Peripheral Benzodiazepine Receptor Pharmacol. Rev., December 1, 1999; 51(4): 629 - 650. [Abstract] [Full Text] [PDF]

				H. Li, Z.-x. Yao, B. Degenhardt, G. Teper, and V. Papadopoulos Cholesterol binding at the cholesterol recognition/ interaction amino acid consensus (CRAC) of the peripheral-type benzodiazepine receptor and inhibition of steroidogenesis by an HIV TAT-CRAC peptide PNAS, January 30, 2001; 98(3): 1267 - 1272. [Abstract] [Full Text] [PDF]