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Polyunsaturated fatty acids (PUFAs) metabolism-driven inflammation is a causative factor in cancer development. However, the function of PUFAs\u2032 metabolism in BC remains largely unknown. Here we report the role and underlying mechanism of epoxyoctadecenoic acids (EpOMEs), the metabolites of linoleic acid mediated by cytochrome P450 (CYP) monooxygenases, in promoting the development of BC, particularly triple-negative BC (TNBC). A metabolomics study identified that EpOMEs were significantly increased in the plasma of BC patients and MMTV-PyMT mice, which accounted for the upregulation of CYP2J2 in BC tumor tissues and tumor cells. Decreased EpOMEs by treatment of CYP monooxygenase inhibitors significantly alleviated tumor development in MMTV-PyMT mice. Treatment with EpOMEs and overexpression of <jats:italic>CYP2J2<\/jats:italic> to increase EpOMEs in TNBC cells significantly promoted cellular proliferation, migration, tumor growth, and metastasis. Whereas knockdown of <jats:italic>CYP2J2<\/jats:italic> to decrease EpOMEs inhibited tumorigenesis and lung metastasis of TNBC, which was reversed by EpOME administration. Transcriptomics and proteomics analyses revealed <jats:italic>CXCL9<\/jats:italic> and PLEC were critical for EpOME-mediated promotion of TNBC. Knockdown of <jats:italic>CXCL9<\/jats:italic> and <jats:italic>PLEC<\/jats:italic> inhibited TNBC progression and EpOME-mediated promotion of TNBC. Both overexpression of <jats:italic>CYP2J2<\/jats:italic> and EpOME treatment upregulate PLEC, while PLEC upregulates NF\u03baB1, which is a transcription regulator of <jats:italic>CXCL9<\/jats:italic>. This study extends the understanding of the function of PUFAs metabolism in BC development, providing potential therapeutic targets and dietary guidelines for patients with TNBC and other BCs.<\/jats:p>","DOI":"10.1038\/s41419-024-07300-6","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T17:42:27Z","timestamp":1734543747000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Epoxy metabolites of linoleic acid promote the development of breast cancer via orchestrating PLEC\/NF\u03baB1\/CXCL9-mediated tumor growth and metastasis"],"prefix":"10.1038","volume":"15","author":[{"given":"Kai-Di","family":"Ni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hou-Hua","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ping","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Xian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Jun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Nan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Tong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Zhi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Jin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Dong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wen","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6014-8160","authenticated-orcid":false,"given":"Jianbo","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4370-9445","authenticated-orcid":false,"given":"Zufeng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3018-0335","authenticated-orcid":false,"given":"Jun-Yan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"key":"7300_CR1","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1016\/S0140-6736(16)31891-8","volume":"389","author":"N Harbeck","year":"2017","unstructured":"Harbeck N, Gnant M. 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The animal experiments were conducted in accordance with the protocols approved by the Institutional Animal Care and Use Committee of the Chongqing Medical University (protocol number: IACUC-CQMU-2023-09028), which concurs with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"901"}}