Epigenetic Switch–Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer
Open Access
- 1 September 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (9), 1312-1329
- https://doi.org/10.1158/2159-8290.cd-19-1493
Abstract
Tumor progression upon treatment arises from pre-existing resistant and/or adaptation of persister cancer cells committing to an expansion phase. Here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (TNBC). This is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where DNA hypomethylation over loci enriched in transposable elements (TEs) is compensated by large chromatin domains of H3K27me3 to warrant TE repression. This epigenetic state creates a vulnerability to epigenetic therapy against EZH2, the H3K27me3 methyltransferase, which alleviates TE repression in taxane-resistant TNBC, leading to double-stranded RNA production and growth inhibition through viral mimicry response. Collectively, our results illustrate how epigenetic states over TEs promote cancer progression under treatment and can inform of vulnerabilities to epigenetic therapy.Other Versions
Funding Information
- Terry Fox Research Institute (PPG-1064)
- CIHR (136963, 158225)
- CIHR (363288)
- Canadian Cancer Society (SU2C-AACR-DT-18-15)
- Stand Up To Cancer Canada (# 80550 6730 RR0001)
- SGC (1097737)
- AbbVie Bayer Pharma AG Boehringer Ingelheim Canada Foundation for Innovation Eshelman Institute for Innovation Genome Canada Ontario Genomics Institute (OGI-055)
- Innovative Medicines Initiative (115766)
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