Targeting MUC1-C Inhibits TWIST1 Signaling in Triple-Negative Breast Cancer

• Published in: Molecular cancer therapeutics Vol. 18; no. 10; pp. 1744 - 1754
• Main Authors: Hata, Tsuyoshi, Rajabi, Hasan, Yamamoto, Masaaki, Jin, Caining, Ahmad, Rehan, Zhang, Yan, Kui, Ling, Li, Wei, Yasumizu, Yota, Hong, Deli, Miyo, Masaaki, Hiraki, Masayuki, Maeda, Takahiro, Suzuki, Yozo, Takahashi, Hidekazu, Samur, Mehmet, Kufe, Donald
• Format: Journal Article
• Language: English
• Published: United States 01.10.2019
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-19-0156

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 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.