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CYPD limits HR+ mammary carcinogenesis in mice
Aitziber Buqué1,2, Manuel Beltrán-Visiedo3, Ai Sato4,3
1Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. abuquemartinez@gmail.com.
Cell Death Discovery
|June 10, 2025
Summary
Mice lacking the CYPD protein, a regulator of cell death, showed increased susceptibility to hormone-driven breast cancer. This suggests CYPD acts as a tumor suppressor, potentially through mitochondrial permeability transition-driven necrosis.
Area of Science:
- Cell Biology
- Immunology
- Oncology
Background:
- Mitochondrial permeability transition (MPT)-driven necrosis and necroptosis are regulated cell death pathways influencing inflammation and immune responses.
- Indolent inflammation in cancer is linked to disease progression and treatment resistance, while anti-tumor immunity restrains tumor development.
Purpose of the Study:
- To investigate the role of MPT-driven necrosis and necroptosis regulators in mammary carcinogenesis using a mouse model of human hormone receptor-positive (HR+) breast cancer.
Main Methods:
- Utilized female C57BL/6J mice with whole-body deletions of key regulators: peptidylprolyl isomerase F (Ppif/CYPD) for MPT-driven necrosis, and receptor-interacting serine-threonine kinase 3 (Ripk3) or mixed lineage kinase domain like pseudokinase (Mlkl) for necroptosis.
- Induced mammary carcinogenesis using medroxyprogesterone acetate (MPA) and 7,12-dimethylbenz[a]anthracene (DMBA).
Main Results:
- Mice with a whole-body deletion of Ppif (CYPD) exhibited increased susceptibility to MPA/DMBA-driven mammary carcinogenesis compared to wild-type controls.
- Mice with systemic defects in Ripk3 or Mlkl (necroptosis regulators) did not show altered susceptibility to carcinogenesis.
Conclusions:
- CYPD acts as an oncosuppressive protein that restrains hormone receptor-positive (HR+) mammary carcinogenesis in mice.
- The tumor-suppressive function of CYPD may be mediated through MPT-driven necrosis.
