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Open AccessArticle

Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer

1
Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
2
Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan
3
Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 402, Taiwan
4
Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan
5
PhD Program in Translational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 199; https://doi.org/10.3390/cancers12010199
Received: 14 November 2019 / Revised: 4 January 2020 / Accepted: 6 January 2020 / Published: 13 January 2020
Recurrence and metastasis are the main causes of triple-negative breast cancer (TNBC) mortality. On the basis of our clinical cohorts and integrative omics analyses, we hypothesized that understanding the interplay between fatty acid binding protein (FABP) and epoxy-eicosatrienoic acid (EET) driven metastatic progression can uncover a new opportunity for TNBC intervention. In this study, the biological relevance of increased protein expression of CYP2C19, FABP4, and FABP5 in TNBC tumors and in the TNBC cell line (MDA-MB-231), as well as its highly metastatic lung seeking variant (LM6) were delineated from publicly available datasets, shRNA-mediated knockdown, EET supplementation, cancer and stromal cell co-cultures, and an orthotopic and resection xenograft tumor mouse model. We found that the high expression levels of CYP2C19 and FABP4 and FABP5 are critical in TNBC metastatic transformation and stromal cell interactions. Furthermore, EET-associated nuclear translocation of FABP4 and FABP5 and nuclear accumulation of SREBP-2 or PPAR-γ influence TNBC cell proliferation, migratory transformation, and distal metastasis priming. Most notably, we uncovered novel bioefficacy and modes of action of the anticancer drug doxorubicin and a phytogalactolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG), which effectively attenuated TNBC recurrence and lung metastasis through deregulating the FABP/EET dynamics and levels. This study, therefore, introduces a novel approach to combating TNBC by targeting the FABP/EET/CYP-associated metastatic signaling network. View Full-Text
Keywords: triple-negative breast cancer; tumor relapse; metastasis; fatty acid binding protein; phytogalactolipid; doxorubicin triple-negative breast cancer; tumor relapse; metastasis; fatty acid binding protein; phytogalactolipid; doxorubicin
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Apaya, M.K.; Hsiao, P.-W.; Yang, Y.-C.; Shyur, L.-F. Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer. Cancers 2020, 12, 199.

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