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PCBP1-mediated regulation of WNT signaling is critical for breast tumorigenesis

Zhao-Ying Yang1, Wen-Long Zhang2, Cheng-Wei Jiang3

  • 1Department of Breast Surgery, China-Japan Union Hospital of Jilin University, No.126, Xiantai Street, Changchun, Jilin, 130033, China.

Cell Biology and Toxicology
|May 31, 2022
PubMed

Insights

Reduced Poly r(C) binding protein 1 (PCBP1) expression promotes breast cancer growth by increasing regulatory T cells (Tregs) and suppressing cytotoxic T cells. WNT signaling activation inhibits this tumor-promoting effect.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Loss of Poly r(C) binding protein 1 (PCBP1) expression or its post-translational modification by Akt1 is linked to breast cancer metastasis.
  • The precise role of PCBP1 in tumor development remains unclear.

Purpose of the Study:

  • To investigate the role of PCBP1 in breast tumorigenesis and its impact on the tumor microenvironment (TME).
  • To evaluate the therapeutic potential of targeting WNT signaling in PCBP1-deficient breast cancer models.

Main Methods:

  • Utilized a 4T1-Pcbp1-/- xenograft orthotopic mouse model of breast cancer.
  • Administered WNT signaling activator TWS119 and Akt2/Akt3 inhibitor GSK690693.
  • Performed mass cytometry analysis of the TME.
  • Isolated and analyzed cytotoxic T cells from healthy donors.

Main Results:

  • PCBP1 knockdown-induced tumorigenesis was inhibited by TWS119, but not GSK690693.
  • TWS119 treatment increased cytotoxic T cells and decreased regulatory T cells (Tregs) in the TME compared to saline controls.
  • Cytotoxic T cells in control mice were exhausted; TWS119 treatment restored their function and reduced Treg suppressive activity.
  • PCBP1 expression is essential for WNT signaling-mediated inhibition of cytotoxic T cell expansion.

Conclusions:

  • Decreased PCBP1 expression promotes breast tumorigenesis by skewing T cells towards Tregs, suppressing anti-tumor immunity.
  • Targeting WNT signaling with TWS119 can counteract the pro-tumorigenic effects of PCBP1 loss by restoring anti-tumor T cell responses.
Keywords:
Effector T cellsGSK3βPCBP1Regulatory T cellsWNT

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