The Consequences of Soluble Epoxide Hydrolase Deletion on Tumorigenesis and Metastasis in a Mouse Model of Breast Cancer

Int J Mol Sci. 2021 Jul 1;22(13):7120. doi: 10.3390/ijms22137120.


Epoxides and diols of polyunsaturated fatty acids (PUFAs) are bioactive and can influence processes such as tumor cell proliferation and angiogenesis. Studies with inhibitors of the soluble epoxide hydrolase (sEH) in animals overexpressing cytochrome P450 enzymes or following the systemic administration of specific epoxides revealed a markedly increased incidence of tumor metastases. To determine whether PUFA epoxides increased metastases in a model of spontaneous breast cancer, sEH-/- mice were crossed onto the polyoma middle T oncogene (PyMT) background. We found that the deletion of the sEH accelerated the growth of primary tumors and increased both the tumor macrophage count and angiogenesis. There were small differences in the epoxide/diol content of tumors, particularly in epoxyoctadecamonoenic acid versus dihydroxyoctadecenoic acid, and marked changes in the expression of proteins linked with cell proliferation and metabolism. However, there was no consequence of sEH inhibition on the formation of metastases in the lymph node or lung. Taken together, our results confirm previous reports of increased tumor growth in animals lacking sEH but fail to substantiate reports of enhanced lymph node or pulmonary metastases.

Keywords: angiogenesis; cancer metastases; polyunsaturated fatty acid.

MeSH terms

  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinogenesis
  • Cell Proliferation / physiology
  • Cell Transformation, Neoplastic
  • Cytochrome P-450 Enzyme System / metabolism
  • Disease Models, Animal
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / metabolism*
  • Epoxy Compounds / metabolism
  • Fatty Acids, Unsaturated / metabolism
  • Female
  • Gene Deletion
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism


  • Epoxy Compounds
  • Fatty Acids, Unsaturated
  • Cytochrome P-450 Enzyme System
  • Epoxide Hydrolases
  • Ephx2 protein, mouse