PDE7A inhibition suppresses triple-negative breast cancer by attenuating de novo pyrimidine biosynthesis.

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, associated with poor response to therapies and high mortality. We identify that phosphodiesterase 7A (PDE7A) is overexpressed in the majority of TNBCs, and a higher level of PDE7A associates with poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway, via the transcription factor IRF1, stimulates the expression of PDE7A in TNBC cells. PDE7A inhibition attenuates TNBC growth in both cell culture and mouse models of TNBC. Inhibition of PDE7A suppresses de novo pyrimidine biosynthesis, in part through the downregulation of the enzyme dihydroorotate dehydrogenase (DHODH). DHODH suppression attenuates TNBC tumor growth, mirroring the effects of PDE7A inhibition, and ectopic DHODH expression rescues PDE

SUBMITTER: Malvi P 

PROVIDER: S-EPMC12490241 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature