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

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.

MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC

“…EMT also increases the capacity for cells to undergo invasion and to form spheres in non-adherent serum-free culture, which is dependent on the presence of self-renewing stem-like cells (26, 27). Consistent with the induction of ZEB1 and EMT, other work has demonstrated that MUC1-C contributes to the self-renewal of breast and NSCLC stem-like cells (28, 29). Other studies in NSCLC cells harboring EGFR or KRAS mutations have shown that targeting the MUC1-C pathway inhibits their growth as tumors in mice (29, 30).…”

“…Overexpression of MUC1-C has been linked to the induction of EMT, stemness and self-renewal in breast and certain other cancer cells (25, 28). The LIN28B→let-7 pathway has also been shown to confer self-renewal of breast cancer stem-like cells, at least in part through the suppression of HMGA2 (19).…”

“…For re-ChIP analysis, NF-κB complexes from the primary ChIP were eluted and reimmunoprecipitated with anti-MUC1-C antibody as described (28). For real time ChIP qPCRs, the SYBR Green system was used with the ABI Prism 7300 Sequence Detector (Applied Biosystems).…”

“…Notably in this regard, the MUC1-C cytoplasmic domain contains a CQC motif that is necessary for MUC1-C homodimerization and its oncogenic function. Targeting of endogenous MUC1-C with the cell-penetrating peptide GO-203, which blocks MUC1-C homodimerization, has thus been shown to be effective in inhibiting MUC1-C function (25, 28). …”

Cancer stem cells: a challenging paradigm for designing targeted drug therapies

“…Oncomed has recently initiated phase II clinical trials for tarextumab in patients with pancreatic and/or lung cancer. Genus Oncology is targeting Mucin 1 (MUC-1), an oncoprotein that has a pivotal role in tumor progression in AML, multiple myeloma, colon cancer, non-small cell lung carcinoma and breast cancer [149][150][151][152]. The company has recently moved its drug candidate, GO-203-2c, into phase Ib/IIa clinical development.…”