Nrg1 engages a crosstalk between Notch and HER3 pathways to promote malignant tumor progression of breast cancer in diabetes

Abstract

Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, and subsequently promotes tumor progression. However, molecular mechanisms underlying Nrg1 overexpression in response to hyperglycemia remain poorly understood. Hyperglycemia altered active histone modifications at the Nrg1 enhancer through histone modifiers, including P300 and SETD1A, causing the open chromatin structure to form enhanceosome complexes where RBPJ, a NOTCH effector, was recruited to upregulate Nrg1 expression. Cells harboring deletions in RBPJ-binding sites showed that hyperglycemia-controlled Nrg1 levels were downregulated, resulting in decreased tumor growth in vitro and in vivo. Streptozotocin-induced hyperglycemia accelerated tumor growth and lapatinib resistance in mice, whereas combining lapatinib with DAPT ameliorated tumor growth under hyperglycemic conditions by inhibiting NOTCH and EGFR superfamilies. NOTCH activity was correlated with NRG1 levels, and high NRG1 levels predicted poor outcomes, particularly in HER2-positive breast cancer patients. Our findings highlight novel impact of hyperglycemia-linked epigenetic modulation of Nrg1 as a potential therapeutic strategy for treating breast cancer patients with diabetes.