Abstract
e13047 Background: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastases (BM) and a poor prognosis. As the most lethal form of breast cancer, brain metastases 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 metastases (BCBM), but the underlying mechanisms are far from been fully elucidated. Methods: Using public datasets and our single-cell transcriptome sequencing data, we identified and verified the specific down-regulation of RARRES2, a multifunctional adipokine and chemokine, in brain metastases of triple negative breast cancer. We investigated the effect of aberrant RARRES2 expression on brain metastases in both in vitro and in vivo studies. Key signaling pathway components were evaluated using qPCR and Western blot analysis. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. Results: We show for the first time that down-regulation of RARRES2 is specifically associated with BCBM, and that RARRES2 promoted BCBM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain-tropic triple negative breast cancer cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols (TAGs) by regulating PTEN-PI3K-SREBP1 signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment. Conclusions: Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of brain metastases, thereby offering potential therapeutic targets for BCBM in TNBC.
Published Version
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