Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program
Alison Hirukawa1,2, Harvey W Smith1, Dongmei Zuo1
1Goodman Cancer Research Centre, McGill University, Montréal, QC, H3A 1A3, Canada.
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.
Insights
Targeting the epigenetic modifier EZH2 inhibits breast cancer metastasis in Luminal B subtypes. This approach reactivates the FOXC1 gene, a key factor in preventing cancer spread and improving patient outcomes.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Oncology
- Histone Modifications
Background:
- Altered histone modifications are implicated in cancer pathogenesis.
- The role of histone modifiers in breast cancer progression and subtype-specific variations remains unclear.
Purpose of the Study:
- To investigate the contribution of the epigenetic modifier EZH2 to breast cancer progression, particularly in Luminal B subtypes.
- To elucidate the molecular mechanisms by which EZH2 influences metastasis.
- To evaluate EZH2 inhibitors as a therapeutic strategy for Luminal B breast cancer.
Main Methods:
- Utilized a mouse model of breast cancer and patient-derived xenografts of the Luminal B subtype.
- Investigated the effects of genetic or pharmacological targeting of EZH2.
- Defined the molecular mechanism involving EZH2, H3K27me3, and FOXC1 gene regulation.
- Analyzed FOXC1 expression as a predictive marker in Luminal B breast cancer patients.
Main Results:
- Targeting EZH2 significantly reduced metastatic behavior in preclinical models.
- Identified a mechanism where EZH2 represses FOXC1 via H3K27me3, thereby promoting invasion.
- Demonstrated that higher FOXC1 expression predicts better outcomes in Luminal B breast cancer.
Conclusions:
- EZH2 plays a critical role in promoting metastasis in Luminal B breast cancer.
- Reactivating FOXC1 through EZH2 inhibition is a promising therapeutic strategy.
- EZH2 methyltransferase inhibitors offer a viable targeted therapy option for Luminal B breast cancer, addressing a gap in current treatments.
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