TY - JOUR
T1 - Novel C-terminal heat shock protein 90 inhibitors target breast cancer stem cells and block migration, self-renewal, and epithelial–mesenchymal transition
AU - Subramanian, Chitra
AU - Grogan, Patrick T.
AU - Wang, Ton
AU - Bazzill, Joseph
AU - Zuo, Ang
AU - White, Peter T.
AU - Kalidindi, Avinaash
AU - Kuszynski, Dawn
AU - Wang, Grace
AU - Blagg, Brian S.J.
AU - Cohen, Mark S.
N1 - Funding Information:
This work was funded in part by the National Institutes of Health (T32 CA009672 (TW), R01 CA120458, CA120458, CA21356 (MSC and BSJB)], Coller Surgical Society Research Fellowship (TW), the University of Michigan Comprehensive Cancer Center Support Grant P30‐CA‐046592, and the University of Michigan Department of Surgery.
Publisher Copyright:
© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - heat shock protein 90 inhibitor
KW - triple-negative breast cancer
KW - tumor-initiating cells
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U2 - 10.1002/1878-0261.12686
DO - 10.1002/1878-0261.12686
M3 - Article
C2 - 32255264
AN - SCOPUS:85084599717
SN - 1574-7891
VL - 14
SP - 2058
EP - 2068
JO - Molecular Oncology
JF - Molecular Oncology
IS - 9
ER -