RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

作者：Yiqun Li, Fangzhou Sun, Chunxiao Li, Hongnan Mo, Yantong Zhou, Dan Lv, Jingtong Zhai, Haili Qian, Fei Ma · 发表于：Military Medical Research · 年份：2023 · DOI：10.1186/s40779-023-00470-y · 被引用次数：48 · 研究领域：Retinoids in leukemia and cellular processes、Cancer, Lipids, and Metabolism、Cancer Risks and Factors

BACKGROUND: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastasis (BrM) and a poor prognosis. As the most lethal form of breast cancer, BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis (BCBrM), but the underlying mechanisms are far from being fully elucidated. METHODS: Through analysis of BCBrM transcriptome data from mice and patients, and immunohistochemical validation on patient tissues, we identified and verified the specific down-regulation of retinoic acid receptor responder 2 (RARRES2), a multifunctional adipokine and chemokine, in BrM of TNBC. We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. RESULTS: We found that down-regulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTE...