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Epigenetic programs shaping lung-specific metastasis in triple-negative breast cancer

ABSTRACT: Triple-negative breast cancer (TNBC) is a major cause of cancer mortality, with distant metastases, particularly to the lung, presenting a significant clinical challenge. While epigenetic mechanisms like DNA methylation (DNAm) are known to influence TNBC progression, their specific role in driving metastasis remains underexplored. To address this gap, we present a comprehensive multi-omics analysis, integrating epigenomic and transcriptomic profiles from TNBC xenograft models and patient cohorts. Genome-wide DNAm profiling of primary tumors, lymph nodes, and lung metastases revealed pronounced global hypomethylation in lung lesions, consistent with clinical samples. Promoter-methylation changes were enriched in pathways linked to invasion and proliferation, and transcriptomic integration identified 22 epigenetically regulated genes. Among these, elevated AK1, SLC2A5, TPI1, and ZBTB17 expression correlated with a higher risk of lung dissemination. These findings highlight aberrant methylation as a driver of TNBC lung colonization and identify candidate prognostic markers, emphasizing the importance of epigenetic reprogramming in organ-specific metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305869 | GEO | 2026/01/27

REPOSITORIES: GEO

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Project description:Background: More than 90% mortality of triple negative breast cancer (TNBC) patients are attributed to cancer metastasis with organotropism. Lung is the frequent site of TNBC metastasis. However, the precise mechanism of lung-specific metastasis of TNBC, particularly the driving factors, is not well understood. Methods: RNA sequencing was performed to identify patterns of gene expression associated with lung metastatic behavior using 4T1-LM3, 231-LM3 and their parental cells (4T1-P, 231-P). Expressions of RGCC, encoding the completion 32 protein response protein, were detected in TNBC cells and tissues by qRT-PCR, western blotting and IHC. Kinase activity assay were performed to evaluated PLK1 kinase activity and the amount of phosphorylated AMP-activated protein kinase α2 (AMPKα2). RGCC-mediated metabolism was determined by UHPLC system. Oxidative phosphorylation was evaluated by JC-1 staining and oxygen consumption rate (OCR) assay. Fatty acid oxidation assay, NADPH and ROS was applied to measure the status of RGCC-mediated fatty acid oxidation. The chemical sensitivity of cells was evaluated by CCK8 assay. Results: RGCC is aberrantly upregulated in pulmonary metastatic cells. High level of RGCC is significantly related with lung metastasis rather than other organ metastases. RGCC can effectively promote the kinase activity of PLK1, and activated PLK1 phosphorylates AMPKα2 to facilitate TNBC lung metastasis. Mechanistically, Survival and colonization of TNBC cells in the lungs by upregulating oxidative phosphorylation of mitochondria to obtain more energy and promoting fatty acid oxidation to produce abundant NADPH and sustains redox homeostasis, thus prevents excessive accumulation of potentially detrimental ROS in metastatic tumor cells, ultimately establishing metastases. Importantly, targeting RGCC in combination with paclitaxel/carboplatin effectively suppresses pulmonary metastases of TNBC in a mouse model. Conclusions: The enhanced RGCC is closely associated with lung-specific metastasis of TNBC. RGCC leads to activation of AMPKα2 and downstream signaling through RGCC-driven PLK1 activity to facilitate TNBC lung metastasis, which may determine a potential value of RGCC-driven OXPHOS and fatty acid oxidation as an important therapeutic target.

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Epigenetic programs shaping lung-specific metastasis in triple-negative breast cancer

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