Researchers have identified and characterised a set of specific super-enhancers that stimulate the activity of critical breast cancer genes.
Breast cancer is the most common cancer and leading cause of death among women globally. Molecular studies have identified different breast cancer subtypes: luminal, HER2+/ER− and basal like. Around 70% of basal-like tumours are triple-negative (ER-/PR-/HER2-). Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. The main treatment option for TNBC is chemotherapy. Due to the high toxicity associated with this treatment, there is a high demand for novel therapeutic targets for this subtype.
Researchers have identified several genomic alterations that associate with different subtypes of breast cancer. However, the lack of common genetic alterations in TNBC has hindered the ability to develop targeted therapies. In addition, researchers understanding of the breast cancer epigenome across subtypes and how this leads to various phenotypic outcomes remains limited.
In this study, published in Nature Communications, researchers applied integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes. Super-enhancers are large clusters of enhancers that specifically drive distinct expression programs that define cellular identity. By using this multi-omic profiling method, researchers were able to perform in-depth data mining and also build a super-enhancer-target regulatory network for all types of breast cancer.
The team used CRISPR/Cas9-mediated gene editing to identify genes that were specifically regulated by TNBC-specific super-enhancers. These included FOXC1 and MET, which are known to promote cancer growth and associate with worse survival in TNBC patients. Here, the team unveiled overexpression of these key oncogenes within TNBC. They also identified ANLN as a TNBC-specific gene regulated by a super-enhancer. The team found that deletion of ANLN super-enhancer could reduce protein expression and tumour cell growth.
Overall, these findings reveal a TNBC-specific epigenomic landscape which contributes to the dysregulation of oncogene expression within breast cancer tumourigenesis.
Dr Yuet Ming Rebecca Chin, corresponding author, stated:
“These findings demonstrate the power of leveraging the epigenetic landscape to identify novel players in TNBC, paving the way to discover more effective therapeutic targets for this aggressive form of breast cancer.”
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