title: The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer.
abstract: BACKGROUND
  Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC.
  
  
  METHODS
  Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points.
  
  
  RESULTS
  SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134.
  
  
  CONCLUSIONS
  Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC.
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Mehran
authors.initials: M
authors.lastname: Makvandi
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Estifanos D
authors.initials: ED
authors.lastname: Tilahun
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lieberman
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Redmond-Craig
authors.initials: RC
authors.lastname: Anderson
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Chenbo
authors.initials: C
authors.lastname: Zeng
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Kuiying
authors.initials: K
authors.lastname: Xu
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Hou
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: McDonald
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pryma
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Radiology and Division of Nuclear Medicine and Clinical Molecular Imaging, Philadelphia, PA 19104, USA. Electronic address: rmach@mail.med.upenn.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D017480:Receptors, sigma / Q000187:drug effects*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017480:Receptors, sigma; C106107:sigma-2 receptor
keywords: Drug delivery; Sigma-2; Targeted therapy; Triple-negative breast cancer