TY - JOUR
T1 - IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells
AU - Battula, Venkata Lokesh
AU - Nguyen, Khoa
AU - Sun, Jeff
AU - Pitner, Mary Kathryn
AU - Yuan, Bin
AU - Bartholomeusz, Chandra
AU - Hail, Numsen
AU - Andreeff, Michael
N1 - Funding Information:
The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through the Cancer Center Support Grant P30CA016672, and by the Breast Cancer Research Foundation (BCRF, both to MA). The authors would also like to thank Vivian Ruvolo for technical guidance in viral transductions. Time-of-flight mass cytometry was performed at the Flow Cytometry and Cellular Imaging core facility at MD Anderson Cancer Center.
Publisher Copyright:
© Battula et al.
PY - 2017
Y1 - 2017
N2 - We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2- cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%. Likewise, BMS-345541 inhibited BCSC GD3S expression, mammosphere formation, and cell migration/invasion in vitro. Breast tumor-bearing mice treated with BMS-345541 showed a statistically significant decrease in tumor volume and exhibited prolonged survival compared to control mice, with a median survival of 78 d for the BMS-345541- treated group vs. 58 d for the controls. Moreover, in an experimental metastases model, treatment with BMS-345541 reduced the lung metastases by > 5-fold. These data suggest that GD2 expression and function, and NFκB signaling, are related, and they control BCSCs tumorigenic characteristics. Thus, the suppression of NFκB signaling by BMS-345541 is a potentially important advance in controlling breast cancer growth and metastases.
AB - We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2- cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%. Likewise, BMS-345541 inhibited BCSC GD3S expression, mammosphere formation, and cell migration/invasion in vitro. Breast tumor-bearing mice treated with BMS-345541 showed a statistically significant decrease in tumor volume and exhibited prolonged survival compared to control mice, with a median survival of 78 d for the BMS-345541- treated group vs. 58 d for the controls. Moreover, in an experimental metastases model, treatment with BMS-345541 reduced the lung metastases by > 5-fold. These data suggest that GD2 expression and function, and NFκB signaling, are related, and they control BCSCs tumorigenic characteristics. Thus, the suppression of NFκB signaling by BMS-345541 is a potentially important advance in controlling breast cancer growth and metastases.
KW - Breast cancer
KW - Cancer stem cells
KW - GD2
KW - GD3 synthase
KW - NFκB
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U2 - 10.18632/oncotarget.16294
DO - 10.18632/oncotarget.16294
M3 - Article
C2 - 28415808
AN - SCOPUS:85020190996
SN - 1949-2553
VL - 8
SP - 36936
EP - 36949
JO - Oncotarget
JF - Oncotarget
IS - 23
ER -