dc.contributor.author | Subramanian, Chitra | |
dc.contributor.author | Grogan, Patrick T. | |
dc.contributor.author | Wang, Ton | |
dc.contributor.author | Bazzill, Joseph | |
dc.contributor.author | Zuo, Ang | |
dc.contributor.author | White, Peter T. | |
dc.contributor.author | Kalidindi, Avinaash | |
dc.contributor.author | Kuszynski, Dawn | |
dc.contributor.author | Wang, Grace | |
dc.contributor.author | Blagg, Brian S. J. | |
dc.contributor.author | Cohen, Mark S. | |
dc.date.accessioned | 2022-09-06T14:20:39Z | |
dc.date.available | 2022-09-06T14:20:39Z | |
dc.date.issued | 2020-04-07 | |
dc.identifier.citation | Subramanian, C., Grogan, P.T., Wang, T., Bazzill, J., Zuo, A., White, P.T., Kalidindi, A., Kuszynski, D., Wang, G., Blagg, B.S.J. and Cohen, M.S. (2020), Novel C-terminal heat shock protein 90 inhibitors target breast cancer stem cells and block migration, self-renewal, and epithelial–mesenchymal transition. Mol Oncol, 14: 2058-2068. https://doi.org/10.1002/1878-0261.12686 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/33418 | |
dc.description.abstract | In patients with triple-negative breast cancer (TNBC), evidence suggests that tumor-initiating cells (TIC) have stem cell-like properties, leading to invasion and metastasis. HSP90 plays a critical role in the conformational maintenance of many client proteins in TIC development. Therefore, we hypothesize that the novel C-terminal HSP90 inhibitors KU711 and KU758 can target TIC and represent a promising strategy for overcoming metastasis. Human breast cancer cells (MDA-MB-468LN, MDA-MB-231) treated with the HSP90 inhibitors KU711, KU758, and 17-AAG showed a 50–80% decrease in TIC markers CD44 and aldehyde dehydrogenase (P < 0.01) as assessed by flow cytometry. A decrease in sphere formation, which was used to assess self-renewal, was observed after the treatment of TNBC cells starting at 2.5 µm KU711 and 0.31 µm KU758. KU compounds also blocked the invasion and migration of TNBC cells in a dose-dependent manner. The knockdown of HSP90 clients was observed without any change in prosurvival HSP70 levels. In vivo, in a murine orthotopic breast cancer model, treatment with KU758 and KU711 yielded an approximately twofold and a fourfold reduction in tumor volumes versus control, respectively, without demonstrated toxicity. In conclusion, C-terminal HSP90 inhibitors are potent novel therapeutics against TNBC in vitro and in vivo as they target TICs and block invasion, EMT transition, and self-renewal. | en_US |
dc.publisher | Wiley Open Access | en_US |
dc.rights | © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Heat shock protein 90 inhibitor | en_US |
dc.subject | Triplenegative breast cancer | en_US |
dc.subject | Tumor-initiating cells | en_US |
dc.title | Novel C-terminal heat shock protein 90 inhibitors target breast cancer stem cells and block migration, self-renewal, and epithelial–mesenchymal transition | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Blagg, Brian Scott | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1002/1878-0261.12686 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-1871-2834 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-4075-8786 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess | en_US |