Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells.
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.
Dana-Farber Cancer Institute Harvard Medical School Boston, MA.
Maroof
M
Alam
Hasan
H
Rajabi
Rehan
R
Ahmad
Caining
C
Jin
Donald
D
Kufe
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D016209:Interleukin-8; D018396:Mucin-1; D016328:NF-kappa B; D010455:Peptides; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; C060192:MUC1 protein, human; C508053:ERBB2 protein, human