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

Tsuyoshi Hata1, Hasan Rajabi1, Masaaki Yamamoto1

  • 1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Molecular Cancer Therapeutics
|July 17, 2019
PubMed

Insights

MUC1-C protein drives TWIST1, promoting triple-negative breast cancer (TNBC) progression, stemness, and drug resistance. Targeting MUC1-C reverses paclitaxel resistance, offering a therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Aberrant expression of MUC1-C and TWIST1 is observed in triple-negative breast cancer (TNBC).
  • No prior association between MUC1-C and TWIST1 in TNBC or other cancers was established.
  • Understanding molecular drivers of TNBC plasticity and drug resistance is critical.

Purpose of the Study:

  • To investigate the functional association between MUC1-C and TWIST1 in TNBC.
  • To elucidate the role of the MUC1-C/TWIST1 axis in driving epithelial-mesenchymal transition (EMT), stemness, and drug resistance.
  • To evaluate MUC1-C as a therapeutic target for overcoming paclitaxel resistance in TNBC.

Main Methods:

  • Investigated MUC1-C activation of STAT3 and subsequent TWIST1 induction.
  • Utilized co-immunoprecipitation to confirm MUC1-C binding to TWIST1.
  • Employed RNA-sequencing (RNA-seq) to analyze EMT gene expression.
  • Assessed cell invasion, self-renewal capacity, and tumorigenicity.
  • Evaluated the effect of targeting MUC1-C on paclitaxel (PTX) resistance.

Main Results:

  • MUC1-C activates STAT3, leading to TWIST1 gene induction.
  • MUC1-C directly binds TWIST1, forming a complex that auto-induces MUC1-C expression.
  • The MUC1-C/TWIST1 circuit drives EMT transcription factors (ZEB1, SNAIL), EMT program genes, cell invasion, stemness markers (SOX2, BMI1, ALDH1, CD44), self-renewal, and tumorigenicity.
  • This circuit is also implicated in acquired paclitaxel resistance.
  • Targeting MUC1-C reverses paclitaxel resistance, showing synergistic effects with PTX in drug-resistant cells.

Conclusions:

  • MUC1-C is a master regulator of TWIST1 induction, EMT, stemness, and drug resistance in TNBC.
  • The MUC1-C/TWIST1 axis represents a critical pathway driving TNBC progression and therapeutic resistance.
  • MUC1-C is a promising therapeutic target for inhibiting TNBC plasticity and overcoming drug resistance.

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