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…
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Hsp70 may promote tumor resistance to therapy.
“the latter of which may promote tumor resistance to therapy (23, 25)”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [25]
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References 59 · Cited by 142
- Authors
- Price, J. T., Quinn, J. M. W., Sims, N. A., Vieusseux, J., Waldeck, K., Docherty, S. E., Myers, D., Nakamura, A., Waltham, M. C., Gillespie, M. T., & Thompson, E. W.
- Affiliations
- 1Tumour Cell Migration and Metastasis Laboratory,
- 2Bone Joint and Cancer Laboratory,
- 6Physiology, and
- 3Pharmacogenomics Laboratory, and
- The University of Melbourne (AU)
- ORCID
- Venue
- Cancer Research
- Published
- 2005-06-01
- Volume
- 65
- Issue
- 11
- Pages
- 4929-4938
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2102392020
- Cited by
- 142
- References
- 59
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 8 · 2016: 3 · 2015: 7 · 2014: 3 · 2013: 8 · 2012: 10
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Victoria University Research Repository (Victoria University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Keywords
- 17-allylamino-17-demethoxygeldanamycin, Hsp90 inhibitors, breast cancer bone metastasis, osteoclastogenesis, osteolysis, RANKL, drug-induced bone loss, radicicol, herbimycin A, trabecular bone volume
- MeSH terms
- Animals, Bone Neoplasms, Breast Neoplasms, Cell Movement, Chemotaxis, Disease Models, Animal, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Osteoclasts, Transplantation, Heterologous, Benzoquinones, Rifabutin, HSP90 Heat-Shock Proteins, Cell Line, Tumor, Lactams, Macrocyclic, Cell Growth Processes, Mice
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