title: Bortezomib enhances the efficacy of fulvestrant by amplifying the aggregation of the estrogen receptor, which leads to a proapoptotic unfolded protein response.
abstract: OBJECTIVE
  Fulvestrant is known to promote the degradation of the estrogen receptor (ER) in the nucleus. However, fulvestrant also promotes the aggregation of the newly synthesized ER in the cytoplasm. Accumulation of protein aggregates leads to cell death but this effect is limited as a result of their elimination by the proteasome. We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death.
  
  
  METHODS
  The rate of aggregation of the ER was monitored in ER(+) breast cancer cells lines, T47D, ZR-75.1, BT474, MDA-MB-361, MCF-7, fulvestrant resistance MCF-7, and tamoxifen-resistant T47D-cyclin D1 cells. Activation of the unfolded protein response, apoptosis, and metabolic rate were also monitored in these cell lines following treatment with fulvestrant, bortezomib, or bortezomib in combination with fulvestrant.
  
  
  RESULTS
  We found that bortezomib enhances the fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking the degradation of the ER in the nucleus. Further, these aggregates activate a sustained unfolded protein response leading to apoptotic cell death. Further, we show that the combination induced tumor regression in a breast cancer mouse model of tamoxifen resistance.
  
  
  CONCLUSIONS
  Adding bortezomib to fulvestrant enhances its efficacy by taking advantage of the unique ability of fulvestrant to promote cytoplasmic aggregates of the ER. As this effect of fulvestrant is independent of the transcriptional activity of the ER, these results suggest that this novel combination may be effective in breast cancers that are ER(+) but estrogen independent.
authors.affiliation: Division of Hematology/Oncology, Tisch Cancer Institute and Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Luena
authors.initials: L
authors.lastname: Papa
authors.forename: Urvashi
authors.initials: U
authors.lastname: Bahadur
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.forename: Julio
authors.initials: J
authors.lastname: Aguirre-Ghiso
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Doris
authors.initials: D
authors.lastname: Germain
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D000077267:Fulvestrant; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001897:Boronic Acids; D011719:Pyrazines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; D000077267:Fulvestrant; D004958:Estradiol; D000069286:Bortezomib