Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells
Metrics: PDF 2355 views | HTML 2106 views | ?
Maroof Alam1,*, Hasan Rajabi1,*, Rehan Ahmad1,2,*, Caining Jin3, and Donald Kufe1
1 Dana-Farber Cancer Institute Harvard Medical School Boston, MA
2 Present address: College of Medicine, King Saud University, Riyadh, Saudi Arabia
3 Present address: Genus Oncology, Boston, MA
* These authors contributed equally to the work
Donald Kufe, email:
Keywords: MUC1, breast cancer, stem-like cells, mammospheres, tumorigenicity, NF-κB.
Received: February 25, 2014 Accepted: March 22, 2014 Published: March 24, 2014
The capacity of breast cancer cells to form mammospheres in non-adherent serum-free culture is used as a functional characteristic of the self-renewing stem-like cell population. The present studies demonstrate that silencing expression of the MUC1-C oncoprotein inhibits growth of luminal MCF-7 and HER2-overexpressing SKBR3 breast cancer cells as mammospheres. We also show that triple-negative MDA-MB-468 breast cancer cells are dependent on MUC1-C for growth as mammospheres and tumor xenografts. Similar results were obtained when MUC1-C function was inhibited by expression of a MUC1-C(CQCAQA) mutant. Moreover, treatment with the MUC1-C inhibitor GO-203, a cell penetrating peptide that binds to the MUC1-C cytoplasmic domain and blocks MUC1-C function, confirmed the importance of this target for self-renewal. The mechanistic basis for these findings is supported by the demonstration that MUC1-C activates NF-κB, occupies the IL-8 promoter with NF-κB, and induces IL-8 transcription. MUC1-C also induces NF-κB-dependent expression of the IL-8 receptor, CXCR1. In concert with these results, targeting MUC1-C with GO-203 suppresses IL-8/CXCR1 expression and disrupts the formation of established mammospheres. Our findings indicate that MUC1-C contributes to the self-renewal of breast cancer cells by activating the NF-κBIL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.