Abstract
Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. Here we report that genetic or pharmacological targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behaviour in both a mouse model of breast cancer and patient-derived xenografts reflective of the Luminal B subtype. We further define a subtype-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, anti-invasive transcriptional program. We demonstrate that higher FOXC1 is predictive of favourable outcome specifically in Luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in Luminal B breast cancer, where options for targeted therapy are limited.
Highlights
Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis
In an effort to unravel the heterogeneity of this disease, global transcriptional profiling has led to the characterization of at least five different intrinsic molecular subtypes of breast cancer; HER2+, Luminal A, Luminal B, Normal-like and Basal-like breast cancer (BLBC)[1]
This work led to the identification of a Luminal Bspecific anti-metastatic transcriptional program centred on the master transcriptional regulator FOXC1, which is silenced in these tumours in an Ezh2-dependent manner
Summary
Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. Given that the behaviour of Ezh[2] is context-dependent, in this study we investigated the role of Ezh[2] in Luminal B breast cancer To this end, we employed a transgenic mouse model to examine the effects of Ezh[2] ablation at each stage of tumorigenesis from early hyperplastic lesions to invasive metastatic disease. Pharmacological inhibitors targeting Ezh[2] de-repressed FOXC1 and reactivated this anti-metastatic program in both murine and human preclinical models, resulting in a dramatic reduction in both the size and number of metastatic lesions This is significant because the vast majority of breast cancer-associated morbidity and mortality are due to distant metastasis. Our findings have important implications for the treatment of Luminal B breast cancer, where a paucity of options for targeted therapy has significantly hindered progress in improving patient outcomes
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