title: Chaperonin Containing TCP-1 Protein Level in Breast Cancer Cells Predicts Therapeutic Application of a Cytotoxic Peptide.
abstract: OBJECTIVE
  Metastatic disease is a leading cause of death for patients with breast cancer, driving the need for new therapies. CT20p is a peptide previously discovered by our group that displays cancer-specific cytotoxicity. To design the optimal therapeutic use of the peptide, we identified the intracellular target of CT20p in breast cancer cells, correlating expression patterns of the target with susceptibility to CT20p.
  
  
  METHODS
  Using polymeric nanoparticles to deliver CT20p, we assessed cytoskeletal changes, cell migration, adhesion, and viability in cells treated with the peptide. Protein pull-down experiments, coupled to mass spectrometry, enabled identification of the peptide's intracellular target. Biochemical and histologic techniques validated target identity in human cell lines and breast cancer tissue microarrays and revealed susceptibility patterns to CT20p.
  
  
  RESULTS
  Chaperonin containing TCP-1 (CCT) was identified as the intracellular target of CT20p. Cancer cells susceptible to CT20p had increased CCT, and overexpression of CCTβ, a subunit of the CCT complex, enhanced susceptibility to CT20p. Susceptible cells displayed reduced tubulin, a substrate of CCT, and inhibition of migration upon CT20p treatment. CCTβ levels were higher in invasive ductal carcinomas than in cancer adjacent tissues and increased with breast cancer stage. Decreased breast cancer patient survival correlated with genomic alternations in CCTβ and higher levels of the chaperone.
  
  
  CONCLUSIONS
  Increased CCT protein in breast cancer cells underlies the cytotoxicity of CT20p. CCT is thus a potential target for therapeutic intervention and serves as a companion diagnostic to personalize the therapeutic use of CT20p for breast cancer treatment. Clin Cancer Res; 22(17); 4366-79. ©2016 AACR.
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida.
authors.forename: Rania
authors.initials: R
authors.lastname: Bassiouni
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida.
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Nemec
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida.
authors.forename: Ashley
authors.initials: A
authors.lastname: Iketani
authors.affiliation: Nanoscience Technology Center, University of Central Florida, Orlando, Florida.
authors.forename: Orielyz
authors.initials: O
authors.lastname: Flores
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida.
authors.forename: Anne
authors.initials: A
authors.lastname: Showalter
authors.affiliation: Orlando VA Medical Center, Orlando, Florida.
authors.forename: Amr S
authors.initials: AS
authors.lastname: Khaled
authors.affiliation: Orlando VA Medical Center, Orlando, Florida.
authors.forename: Priya
authors.initials: P
authors.lastname: Vishnubhotla
authors.affiliation: Proteomics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sprung
authors.affiliation: Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Kaittanis
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Perez
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida. annette.khaled@ucf.edu.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Khaled
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056404:Chaperonin Containing TCP-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053758:Nanoparticles; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011108:Polymers; D011379:Prognosis; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D011108:Polymers; D021122:Protein Subunits; D056404:Chaperonin Containing TCP-1