A research team led by biologists at City University of Hong Kong (CityU) has identified a set of specific super-enhancers that stimulate the activity of the Triple-Negative Breast Cancer (TNBC) genes, and that deleting certain specific super-enhancers can reduce tumour growth. The findings may help discover new effective drug targets for TNBC patients to improve their survival chance.  

Led by Dr Wang Xin, Associate Head, and Dr Rebecca Chin Yuet-ming, Assistant Professor, in the Department of Biomedical Sciences, the research has been published in Nature Communications under the title “Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling”.

TNBC is an aggressive type of breast cancer with a poor prognosis and a high fatality rate. Chemotherapy is currently the major treatment option but the clinical result is unsatisfactory.

Traditionally, cancer research has focused on identifying gene mutations in different types of breast cancer. However, how the epigenetic circuit affects cancer remains poorly characterised.

While genetic mutation is a change in one or more parts of the DNA sequence, an epigenetic change also changes a gene’s DNA, but not at the sequence level. Instead, special marks called epigenetic marks, are added to or removed from the DNA sequence to change how a protein works in the body. Specific epigenetic marks are contained in super-enhancers. Deregulation, meaning abnormal regulation, of super-enhancers can therefore induce high production of cancer driver proteins and promote cancer formation.

To find out how these super-enhancers can affect TNBC cells’ growth, the team used the method of multiomic profiling to perform in-depth data mining and built a specific super-enhancer-target regulatory network for all types of breast cancer by integrating multi-level epigenomic sequencing data for 21 cell lines with gene expression data and clinical information for over 4,000 patient samples.

“Based on the regulatory network, we identify the gene FOXC1 as a key regulator of cancer growth and metastasis that is driven by a TNBC-specific super-enhancer. We have also demonstrated that super-enhancer drives FOXC1 expression, and importantly, enhances cancer growth in mouse models,” said Dr Wang.

The researchers went a step further and applied the integrated method to discover another new TNBC-specific gene ANLN, which has been shown in previous studies to be correlated with TNBC recurrence and poor survival rates.

In this study, the team found that the deletion of super-enhancer of ANLN could reduce the protein expression and tumour cell growth. “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,” Dr Chin said.

“We hope this research will contribute to the development of effective drugs for TNBC patients and improve their chances of survival,” she added.

Huang Hao, PhD student and Dr Hu Jianyang, postdoctoral fellow from CityU’s BMS are the co-first authors of the study. Dr Chan Kui-ming and Dr Zhang Liang from BMS co-authored the study. Scientists from Queen Elizabeth Hospital of Hong Kong and The Affiliated Tumor Hospital of Guangxi Medical University also contributed.