Oncotarget

Research Papers:

Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells

Maroof Alam, Hasan Rajabi, Rehan Ahmad, Caining Jin and Donald Kufe _

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Oncotarget. 2014; 5:2622-2634. https://doi.org/10.18632/oncotarget.1848

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Abstract

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

Correspondence:

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

Abstract

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(CQCAQA) 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-κBIL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population.


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