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

Parmanand Malvi1, Suresh Bugide1, Roshan Dutta1

  • 1Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35233, USA.

Cell Reports. Medicine
|September 17, 2025
PubMed

Insights

Phosphodiesterase 7A (PDE7A) is overexpressed in triple-negative breast cancer (TNBC) and drives tumor growth by promoting pyrimidine synthesis. Inhibiting PDE7A or dihydroorotate dehydrogenase (DHODH) shows therapeutic promise for TNBC.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Triple-negative breast cancer (TNBC) is aggressive with poor therapeutic response and high mortality.
  • Phosphodiesterase 7A (PDE7A) is frequently overexpressed in TNBC, correlating with poor prognosis.

Purpose of the Study:

  • To investigate the role of PDE7A in TNBC progression and its therapeutic potential.
  • To elucidate the molecular pathway regulated by PDE7A in TNBC.

Main Methods:

  • Analysis of PDE7A expression in TNBC patient samples and cell/mouse models.
  • Investigating the PI3K/AKT/IRF1 pathway's regulation of PDE7A.
  • Assessing the impact of PDE7A inhibition on TNBC growth and pyrimidine biosynthesis.
  • Evaluating the role of dihydroorotate dehydrogenase (DHODH) in PDE7A-mediated effects.

Main Results:

  • PDE7A overexpression is linked to poor TNBC prognosis.
  • The PI3K/AKT pathway, via IRF1, upregulates PDE7A in TNBC.
  • PDE7A inhibition reduces TNBC growth by suppressing de novo pyrimidine biosynthesis, partly via DHODH downregulation.
  • DHODH suppression mimics PDE7A inhibition's anti-tumor effects, and its restoration rescues these effects.

Conclusions:

  • The PDE7A → DHODH → de novo pyrimidine biosynthesis pathway is a critical driver of TNBC.
  • Co-targeting PDE7A and DHODH offers a potent therapeutic strategy for TNBC.
  • This study identifies novel therapeutic targets for aggressive TNBC subtypes.
Keywords:
DHODHPDE7Aphosphodiesterasespyrimidine biosynthesistriple-negative breast cancer

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