title: In vitro and in vivo application of radiolabeled gastrin-releasing peptide receptor ligands in breast cancer.
abstract: Breast cancer (BC) consists of multiple subtypes defined by various molecular characteristics, for instance, estrogen receptor (ER) expression. Methods for visualizing BC include mammography, MR imaging, ultrasound, and nuclear medicine-based methods such as (99m)Tc-sestamibi and (18)F-FDG PET, unfortunately all lacking specificity. Peptide receptor scintigraphy and peptide receptor radionuclide therapy are successfully applied for imaging and therapy of somatostatin receptor-expressing neuroendocrine tumors using somatostatin receptor radioligands. On the basis of a similar rationale, radioligands targeting the gastrin-releasing peptide receptor (GRP-R) might offer a specific method for imaging and therapy of BC. The aim of this study was to explore the application of GRP-R radioligands for imaging and therapy of BC by introducing valid preclinical in vitro and in vivo models.
  
  
  METHODS
  GRP-R expression of 50 clinical BC specimens and the correlation with ER expression was studied by in vitro autoradiography with the GRP-R agonist (111)In-AMBA. GRP-R expression was also analyzed in 9 BC cell lines applying (111)In-AMBA internalization assays and quantitative reverse transcriptase polymerase chain reaction. In vitro cytotoxicity of (177)Lu-AMBA was determined on the GRP-R-expressing BC cell line T47D. SPECT/CT imaging and biodistribution were studied in mice with subcutaneous and orthotopic ER-positive T47D and MCF7 xenografts after injection of the GRP-R antagonist (111)In-JMV4168.
  
  
  RESULTS
  Most of the human BC specimens (96%) and BC cell lines (6/9) were found to express GRP-R. GRP-R tumor expression was positively (P = 0.026, χ(2)(4) = 12,911) correlated with ER expression in the human BC specimens. Treatment of T47D cells with 10(-7) M/50 MBq of (177)Lu-AMBA resulted in 80% reduction of cells in vitro. Furthermore, subcutaneous and orthotopic tumors from both BC cell lines were successfully visualized in vivo by SPECT/CT using (111)In-JMV4168; T47D tumors exhibited a higher uptake than MCF7 xenografts.
  
  
  CONCLUSIONS
  Targeting GRP-R-expressing BC tumors using GRP-R radioligands is promising for nuclear imaging and therapy, especially in ER-positive BC patients.
authors: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands s.dalm@erasmusmc.nl.
authors: Simone U
authors: SU
authors: Dalm
authors: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC, Rotterdam, The Netherlands.
authors: John W M
authors: JW
authors: Martens
authors: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC, Rotterdam, The Netherlands.
authors: Anieta M
authors: AM
authors: Sieuwerts
authors: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors: Carolien H M
authors: CH
authors: van Deurzen
authors: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Stuart J
authors: SJ
authors: Koelewijn
authors: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Erik
authors: E
authors: de Blois
authors: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Athens, Greece; and.
authors: Theodosia
authors: T
authors: Maina
authors: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Athens, Greece; and.
authors: Berthold A
authors: BA
authors: Nock
authors: Institut des Biomolécules Max Mousseron, UMR5247, CNRS-UM1-UM2, Montpellier, France.
authors: Luc
authors: L
authors: Brunel
authors: Institut des Biomolécules Max Mousseron, UMR5247, CNRS-UM1-UM2, Montpellier, France.
authors: Jean-Alain
authors: JA
authors: Fehrentz
authors: Institut des Biomolécules Max Mousseron, UMR5247, CNRS-UM1-UM2, Montpellier, France.
authors: Jean
authors: J
authors: Martinez
authors: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Marion
authors: M
authors: de Jong
authors: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Marleen
authors: M
authors: Melis
mesh_terms: D000818:Animals; D001839:Bombesin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use; D007553:Isotope Labeling; D008024:Ligands; D051379:Mice; D018004:Receptors, Bombesin / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D007205:Indium Radioisotopes; D008024:Ligands; D018004:Receptors, Bombesin; D001839:Bombesin
keywords: AMBA; GRP-R; JMV4168; PRS/PRRT; breast cancer