In a new study published in Nature, researchers investigated the molecular mechanisms behind the epigenetic regulation of the NRG1 enhancer that drives NRG1 overexpression in breast cancer cells under hyperglycaemic conditions.
Breast cancer is the second leading cause of cancer-related deaths in Western countries. Hyperglycaemia, a hallmark of diabetes, is associated with an increased risk of breast cancer development and poor disease outcome. Neuregulin 1 (NRG1) is a member of the epidermal growth factor family, plays a role in proliferation and differentiation and is a key mediator linking hyperglycaemic memory in breast cancer cells to malignant tumour progression. It contributes to malignant tumour development and is considered both an oncogene and a tumour suppressor gene. The molecular mechanisms behind hyperglycaemia-induced NRG1 overexpression in breast cancer remain poorly understood.
NRG1 is key
In this study, researchers used high glucose-adapted cancer cells and mouse models with modest-temporary hyperglycaemia and methods such as ChIP-qPCR and bisulphite sequencing to show that hyperglycaemia causes active histone modifications at the NRG1 enhancer. They then showed that this leads to the recruitment of RBPJ, E1A binding protein p300, and SET domain containing 1A to the NRG1 enhancer region to form a protein complex (enhanceosome) which upregulates NRG1 expression.
Using CRISPR/Cas9 genome editing, researchers deleted RBPJ-binding sites, which led to a decrease in hyperglycaemia-controlled NRG1 levels and a decrease in tumour growth in vitro and in vivo. Mice with modest-temporary hyperglycaemia showed accelerated tumour growth and resistance to lapatinib, a drug commonly used to treat breast cancer. However, combining lapatinib with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S42 phenylglycine t-butyl ester (DAPT) ameliorated tumour growth under hyperglycaemic conditions by inhibiting NOTCH and epidermal growth factor receptor superfamilies. NOTCH activity was found to be correlated with NRG1 levels, and high NRG1 levels were predictive of poor outcomes, especially in HER2-positive breast cancer patients (HER2 is a protein that helps breast cancer cells grow quickly).
A new treatment for breast cancer?
The findings of this study have important implications for the understanding of the mechanisms underlying the regulation of NRG1 expression. By understanding the molecular mechanisms behind NRG1 overexpression in hyperglycaemic conditions, researchers aim to develop new treatments. In the future, new therapeutic strategies aimed at modulating the epigenetic control of NRG1 expression could potentially be used to treat breast cancer in patients with diabetes and overcome drug resistance and breast cancer recurrence. Further studies are needed to fully understand the potential implications of these findings and to determine their clinical significance.