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Epigenetic programs shaping lung metastasis in triple-negative breast cancer
Diego Marzese1, Andres Bedoya-Lopez, Javier Orozco
1IdISBa.
Abstract:
Triple-negative breast cancer (TNBC) is a major cause of cancer mortality, with distant metastases presenting a significant clinical challenge. While epigenetic mechanisms like DNA methylation are known to influence TNBC progression, their specific role in driving metastasis remains underexplored. To address this gap, we performed comprehensive multi-omics analysis, integrating epigenomic and transcriptomic profiles from TNBC xenograft models and patient cohorts. Genome-wide DNA methylation profiling of primary tumors, lymph nodes, and lung metastases from xenografts revealed pronounced global hypomethylation in lung lesions, consistent with findings from the clinical cohort. 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 altered DNA methylation as a driver of TNBC lung colonization and identify candidate prognostic markers, emphasizing the importance of epigenetic reprogramming in organ-specific lung metastases.
Insights
Triple-negative breast cancer (TNBC) lung metastasis is driven by altered DNA methylation. Global hypomethylation in lung lesions and specific gene changes highlight epigenetic reprogramming
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Triple-negative breast cancer (TNBC) is a leading cause of cancer mortality.
- Distant metastasis, particularly to the lungs, poses a significant clinical challenge in TNBC.
- The role of epigenetic alterations, like DNA methylation, in driving TNBC metastasis is not fully understood.
Purpose of the Study:
- To investigate the role of DNA methylation in driving lung metastasis of TNBC.
- To identify specific epigenetic changes and genes associated with TNBC lung colonization.
- To explore potential prognostic markers for TNBC lung dissemination.
Main Methods:
- Comprehensive multi-omics analysis integrating epigenomic and transcriptomic data.
- Genome-wide DNA methylation profiling of TNBC xenograft models (primary tumors, lymph nodes, lung metastases).
- Analysis of DNA methylation and gene expression in a clinical TNBC patient cohort.
Main Results:
- Pronounced global hypomethylation observed in lung metastases from xenografts, consistent with clinical data.
- DNA methylation changes in promoter regions were enriched in pathways related to invasion and proliferation.
- Identified 22 epigenetically regulated genes, with elevated expression of AK1, SLC2A5, TPI1, and ZBTB17 correlating with increased lung metastasis risk.
Conclusions:
- Altered DNA methylation patterns are a key driver of TNBC lung colonization.
- Epigenetic reprogramming plays a critical role in organ-specific metastasis.
- AK1, SLC2A5, TPI1, and ZBTB17 represent potential prognostic markers for TNBC lung dissemination.
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