Abstract
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.
Highlights
Breast cancer stem cells (BCSCs) are a subpopulation of primary breast tumor cells that are resistant to most conventional chemotherapeutic agents, and they can cause secondary primary tumors if they are not eradicated from the body via surgery or radiotherapy [1, 2]
We show that NFκB signaling is activated in GD2+ BCSCs and that the inhibition of this signaling by the IKKα/β inhibitor BMS-345541 suppresses BCSC tumorigenic functions, including metastasis
To investigate if GD2 and GD3 synthase (GD3S) expression was dependent on NFκB signaling, we knocked down IKKα, in MDA-MB-231 using shRNA (Figure 2C). mRNA and protein expression analysis validated inhibition of IKKα expression by 70 to 90% in IKKα knock-down, compared to control, cells (Figure 2C through 2E)
Summary
Breast cancer stem cells (BCSCs) are a subpopulation of primary breast tumor cells that are resistant to most conventional chemotherapeutic agents, and they can cause secondary primary tumors if they are not eradicated from the body via surgery or radiotherapy [1, 2]. These cells can cause tumor metastasis through their ability to dissociate from the primary tumor and invade vicinal tissues and vasculature [3]. Inhibition of GD3S expression reduced lung metastases of breast cancer cells in immunodeficient mice [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
