Targeting MUC1-C inhibits TWIst1 signaling in triple-negative breast cancer

Tsuyoshi Hata, Hasan Rajabi, Masaaki Yamamoto, Caining Jin, Rehan Ahmad, Yan Zhang, Ling Kui, Wei Li, Yota Yasumizu, Deli Hong, Masaaki Miyo, Masayuki Hiraki, Takahiro Maeda, Yozo Suzuki, Hidekazu Takahashi, Mehmet Samur, Donald Kufe

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Abstract

The oncogenic MUC1-C protein and the TWIST1 epithelial–mesenchymal transition transcription factor (EMT-TF) are aberrantly expressed in triple-negative breast cancer (TNBC) cells. However, there is no known association between MUC1-C and TWIST1 in TNBC or other cancer cells. Here, we show that MUC1-C activates STAT3, and that MUC1-C and pSTAT3 drive induction of the TWIST1 gene. In turn, MUC1-C binds directly to TWIST1, and MUC1-C/TWIST1 complexes activate MUC1-C expression in an autoinductive circuit. The functional significance of the MUC1-C/TWIST1 circuit is supported by the demonstration that this pathway is sufficient for driving (i) the EMT-TFs, ZEB1 and SNAIL, (ii) multiple genes in the EMT program as determined by RNA-seq, and (iii) the capacity for cell invasion. We also demonstrate that the MUC1-C/TWIST1 circuit drives (i) expression of the stem cell markers SOX2, BMI1, ALDH1, and CD44, (ii) self-renewal capacity, and (iii) tumorigenicity. In concert with these results, we show that MUC1-C and TWIST1 also drive EMT and stemness in association with acquired paclitaxel (PTX) resistance. Of potential therapeutic importance, targeting MUC1-C and thereby TWIST1 reverses the PTX refractory phenotype as evidenced by synergistic activity with PTX against drug-resistant cells. These findings uncover a master role for MUC1-C in driving the induction of TWIST1, EMT, stemness, and drug resistance, and support MUC1-C as a highly attractive target for inhibiting TNBC plasticity and progression.

Original languageEnglish
Pages (from-to)1744-1754
Number of pages11
JournalMolecular cancer therapeutics
Volume18
Issue number10
DOIs
Publication statusPublished - 2019 Jan 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hata, T., Rajabi, H., Yamamoto, M., Jin, C., Ahmad, R., Zhang, Y., Kui, L., Li, W., Yasumizu, Y., Hong, D., Miyo, M., Hiraki, M., Maeda, T., Suzuki, Y., Takahashi, H., Samur, M., & Kufe, D. (2019). Targeting MUC1-C inhibits TWIst1 signaling in triple-negative breast cancer. Molecular cancer therapeutics, 18(10), 1744-1754. https://doi.org/10.1158/1535-7163.MCT-19-0156