CYPD limits HR mammary carcinogenesis in mice.

Mitochondrial permeability transition (MPT)-driven necrosis and necroptosis are regulated variants of cell death that can drive inflammation or even promote antigen-specific immune responses. In oncological settings, indolent inflammatory reactions have been consistently associated with accelerated disease progression and resistance to treatment. Conversely, adaptive immune responses specific for tumor-associated antigens are generally restraining tumor development and contribute to treatment sensitivity. Here, we harnessed female C57BL/6J mice lacking key regulators of MPT-driven necrosis and necroptosis to investigate whether whole-body defects in these pathways would influence mammary carcinogenesis as driven by subcutaneous slow-release medroxyprogesterone acetate (MPA, M) pellets plus orally administered 7,12-dimethylbenz[a]anthracene (DMBA, D), an in vivo model that recapitulates multiple facets of the biology and immunology of human hormone receptor positive (HR) breast cancer. Our data demonstrate that female mice bearing a whole-body, homozygous deletion in peptidylprolyl isomerase F (Ppif), which encodes a key regulator of MPT-driven necrosis commonly known as CYPD, but not female mice with systemic defects in necroptosis as imposed by the whole body-deletion homozygous of receptor-interacting serine-threonine kinase 3 (Ripk3) or mixed lineage kinase domain like pseudokinase (Mlkl), are more susceptible to M/D-driven carcinogenesis than their wild-type counterparts. These findings point to CYPD as to an oncosuppressive protein that restrains HR mammary carcinogenesis in mice, at least potentially via MPT-driven necrosis.