Neoadjuvant HER2 inhibition induces ESR1 DNA methylation alterations resulting in clinically relevant ER expression changes in breast cancer
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PROVIDER: PRJNA1193004 | ENA |
REPOSITORIES: ENA
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Project description:Divergent estrogen receptor (ER) and HER2 status with breast cancer disease progression has important consequences for clinical management and long-term survival. Molecular subtype expression is dynamic and influenced by therapeutic intervention and the metastatic environment. HER2 status, ER expression levels and global DNA methylation was assessed in pre-treatment biopsies, in post-treatment samples in patients with residual disease and, where relevant, in metastatic tumour samples. Mapping of the methylation landscape revealed global gains in hypomethylation following treatment (n=7 matched tumours, 16 samples) in contrast to hypermethylation on metastasis (n=5 matched tumours, 14 samples). Differential methylation of key signalling pathways, including estrogen response, epithelial to mesenchymal transition and PI3K/AKT/mTOR, is conserved between post-treatment and metastasis. However, where core pathway genes were hypomethylated following treatment, there was a shift to hypermethylation on metastasis, facilitating alterations in the tumour phenotype. This study unlocks DNA methylation as a key process in breast cancer progression providing vital insights into the effects of targeted HER2 treatment. This work provides a clear rationale to develop combined HER2 inhibitor and endocrine therapeutic strategies to enhance long-term survival in HER2 positive patients.
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