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Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer

Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer image
Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer image
Current prognostic tools and targeted therapeutic approaches have limited value for metastatic triple negative breast cancer (TNBC). There is an ultimate need to provide novel and effective avenues for molecular stratification and personalized therapy for TNBC patients. We hypothesized that uncovering the role of oxylipins, a class of bioactive lipids derived by the action of CYP450 cyclooxygenases and lipoxygenases may offer new insight towards this direction. In this study, we utilized integrative genomics, proteomics and oxylipin metabolomics technology platform to decipher the potential theranostic roles of oxylipins in TNBC. Patient-derived tissue specimens, public cohorts, i.e., The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and a panel of mammary-derived cell lines were utilized in this study. Comparison of oxylipin metabolome profile, tumor tissue immunoreactivity, and gene expression analyses showed that arachidonic acid epoxygenation products, epoxyeicosatrienoic acid metabolites (EETs), by CYP epoxygenases are strongly associated with TNBC metastasis. We further identified EETs as metastasis drivers in mesenchymal-like TNBC cells. Pathway networking analysis revealed that, in hormone-positive breast cancer subtype, CYP epoxygenase overexpression is more related to immune cell-associated signaling, while EET-mediated Myc, Ras, MAPK, EGFR, HIF-1α, and NOD1/2 signaling are the molecular vulnerabilities of metastatic CYP epoxygenase-overexpressing TNBC tumors. This study identifies a special stratification of triple negative breast tumors according to their EET metabolite ratio classifiers and CYP epoxygenase profiles that may provide a useful prognostic and therapeutic target for the development of personalized intervention strategy for TNBC.

Apaya MK, Shiau JY, Liao GS, Liang YJ, Chen CW, Yang HC, Chu CH, Yu JC, Shyur LF* (2019) Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer J Exp Clin Cancer Res, 38(1):187