title: The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line.
abstract: Breast cancer metastasis to the bone occurs frequently, causing numerous complications including severe pain, fracture, hypercalcemia, and paralysis. Despite its prevalence and severity, few effective therapies exist. To address this, we examined whether the heat shock protein 90 (Hsp90) inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), would be efficacious in inhibiting breast cancer metastasis to bone. Utilizing the human breast cancer subline, MDA-MB-231SA, previously in vivo selected for its enhanced ability to generate osteolytic bone lesions, we determined that 17-AAG potently inhibited its in vitro proliferation and migration. Moreover, 17-AAG significantly reduced MDA-MB-231SA tumor growth in the mammary-fat pad of nude mice. Despite these findings, 17-AAG enhanced the incidence of bone metastasis and osteolytic lesions following intracardiac inoculation in the nude mouse. Consistent with these findings, 17-AAG enhanced osteoclast formation 2- to 4-fold in mouse bone marrow/osteoblast cocultures, receptor activator of nuclear factor kappaB ligand (RANKL)-stimulated bone marrow, and RAW264.7 cell models of in vitro osteoclastogenesis. Moreover, the drug enhanced osteoclastogenesis in human cord blood progenitor cells, demonstrating that its effects were not limited to mouse models. In addition to 17-AAG, other Hsp90 inhibitors, such as radicicol and herbimycin A, also enhanced osteoclastogenesis. A pro-osteolytic action of 17-AAG independent of tumor presence was also determined in vivo, in which 17-AAG-treated tumor-naive mice had reduced trabecular bone volume with an associated increase in osteoclast number. Thus, HSP90 inhibitors can stimulate osteoclast formation, which may underlie the increased incidence of osteolysis and skeletal tumor incidence caused by 17-AAG in vivo. These data suggest an important contraindication to the Hsp90 targeted cancer therapy currently undergoing clinical trial.
authors.affiliation: Tumour Cell Migration and Metastasis Laboratory, St. Vincent's Institute, Melbourne, Vistoria, Australia. jprice@svi.edu.au
authors.forename: John T
authors.initials: JT
authors.lastname: Price
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Quinn
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.forename: Jessica
authors.initials: J
authors.lastname: Vieusseux
authors.forename: Kelly
authors.initials: K
authors.lastname: Waldeck
authors.forename: Susan E
authors.initials: SE
authors.lastname: Docherty
authors.forename: Damian
authors.initials: D
authors.lastname: Myers
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.forename: Mark C
authors.initials: MC
authors.lastname: Waltham
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Gillespie
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
mesh_terms: D000818:Animals; D016227:Benzoquinones; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin