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Updated: Jun 10, 2025

The Use of Mouse Mammary Tumor Cells in an In Vitro Invasion Assay as a Measure of Oncogenic Cell Behavior
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RNA binding protein ZCCHC24 promotes tumorigenicity in triple-negative breast cancer

Yutaro Uchida1, Ryota Kurimoto1, Tomoki Chiba1

  • 1Department of Systems Biomedicine, Institute of Science Tokyo, Tokyo, 113-8510, Japan.

EMBO Reports
|October 17, 2024
PubMed

Insights

Targeting ZCCHC24, an RNA-binding protein, shows therapeutic potential in triple-negative breast cancer (TNBC). Reducing ZCCHC24 levels combats treatment resistance and tumor growth in TNBC models.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cancer Stem Cell Research

Background:

  • Triple-negative breast cancer (TNBC) is aggressive, lacking effective therapeutic targets.
  • Cancer stem-like cells (CSCs) drive TNBC treatment resistance and poor patient outcomes.
  • Targeting CSCs is crucial for improving TNBC patient survival.

Purpose of the Study:

  • To identify novel therapeutic targets within the TNBC CSC population.
  • To investigate the role of RNA-binding protein ZCCHC24 in TNBC tumorigenicity and treatment resistance.

Main Methods:

  • Identification of ZCCHC24 enrichment in mesenchymal-like TNBC cells.
  • Analysis of ZCCHC24's direct binding to mRNA cis-elements (UGUWHWWA) to stabilize target genes.
  • Assessment of ZCCHC24 knockdown effects using siRNAs in TNBC patient-derived xenografts (PDXs).
  • Evaluation of combined ZCCHC24 knockdown and BET inhibitor JQ1 therapy in TNBC PDXs.

Main Results:

  • ZCCHC24 promotes tumorigenicity and treatment resistance by stabilizing specific mRNAs.
  • ZCCHC24 directly binds to UGUWHWWA elements, stabilizing mRNAs of key genes including ZEB1.
  • ZEB1, a ZCCHC24 target, enhances cancer stemness and reciprocally induces ZCCHC24 expression.
  • ZCCHC24 knockdown reduced the mesenchymal-like cell population and demonstrated therapeutic effects in TNBC PDXs.
  • Combined ZCCHC24 knockdown and JQ1 treatment synergistically suppressed tumor growth in TNBC PDXs.

Conclusions:

  • ZCCHC24 is a key driver of TNBC aggressiveness and treatment resistance by regulating CSC-related gene expression.
  • Targeting ZCCHC24 represents a promising therapeutic strategy for TNBC.
  • Combination therapy involving ZCCHC24 inhibition and BET inhibitors may overcome treatment resistance in TNBC.
Keywords:
Breast CancerCancer Stem CellsRNA Binding ProteinZEB1mRNA Stabilization

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