Super-enhancers discovered that may improve breast cancer therapy

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Biologists have discovered novel super-enhancers that may aid in manufacturing therapy for triple-negative breast cancer.

The research conducted by biologists at the City University of Hong Kong (CityU) has distinguished and characterised a set of specific super-enhancers that initiate the activity of critical cancer genes, discovering that eliminating these specific super-enhancers can reduce tumour cell growth.

TNBC: A silent killer

Triple-negative breast cancer (TNBC) is an incredibly aggressive type of breast cancer that carries a considerably high fatality rate ; the standard treatment option of chemotherapy is currently achieving poor results, meaning this discovery could transform cancer treatment.

Breast cancer is the most prevalent type of cancer in women, astoundingly accounting for 10-15%. TNBC is especially hard to detect and target due to not expressing hormone receptors and a protein called Her2.

A new approach to breast cancer research

This new investigation takes a fresh approach to cancer research, which traditionally has analysed gene mutations in different types of breast cancer, with this new study targeting how the epigenetic circuit affects cancers.

Whereas genetic mutation is characterised as a change in one or multiple parts of a DNA sequence, epigenetic modification likewise makes alterations to a gene’s DNA. The distinct difference is that it does do this at a sequence level.

Contrastingly, special marks (epigenetic marks) modify how proteins work in the body by being added or subtracted and are contained in super-enhancers. The abnormal regulation of these subsequently induces the production of cancer-causing driver proteins.

Investigating super-enhancers

To investigate these super-enhancers, the researchers utilised a multi-omic profiling method to conduct in-depth mining data, creating a specific super-enhancer target regulatory network for all forms of breast cancer, supplemented by multi-level epigenomic sequencing data for the 21 cell lines of 4,000 patients genes.

Dr Wang Xin, a computational biologist from the Department of Biomedical Sciences at CityU, said: “Our integrated analyses reveal that the clustering of super-enhancers is sufficient to characterise different subtypes of breast cancer.

“Importantly, based on the regulatory network, we identify the gene FOXC1 as a key regulator of cancer growth and metastasis, which is driven by a TNBC-specific super-enhancer. The FOXC1 is predictive of patients’ survival and help develop therapeutic strategies targeting epigenetic circuits.”

Crucial cancer driver genes such as FOXC1 and MET promote cancer growth and are a significant factor in poor survival rates in TNBC patients; until now, there was very little knowledge of these genes’ high expression in TNBC.

Dr Rebecca Chin Yuet-ming, a cancer biologist from CityU, explained: “Our network biology analysis uncovers FOXC1 as the master regulator of a large set of genes in metastasis. Using CRISPR/Cas9 technology, we further directly demonstrate that super-enhancer drives FOXC1 expression, and importantly, enhances cancer growth in mouse models.”

Discovering a novel gene

In conducting their analysis, the scientists discovered another TNBC-specific gene called ANLN, which has indicated to be influential in TNBC recurrence and low survival rate. They proclaim that deletion of this gene could mitigate protein expression and tumour cell growth.

Dr Chin said: “These findings demonstrate the power of leveraging epigenetic landscape to identify novel players in TNBC, paving the way to discover more effective therapeutic targets for this aggressive form of breast cancer.

“We hope our findings can contribute to the development of effective drugs for TNBC patients to improve their chance of survival.”

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