Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia

Abstract

AbstractHyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia inducesNeuregulin 1(Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-inducedNrg1overexpression remain poorly understood. Here, we show that hyperglycemia causes active histone modifications at theNrg1enhancer, forming enhanceosome complexes where recombination signal binding protein for immunoglobulin kappa J region (RBPJ), E1A binding protein p300 (P300), and SET domain containing 1 A (SETD1A) are recruited to upregulate Nrg1 expression. Deletions in RBPJ-binding sites causes hyperglycemia-controlledNrg1levels to be downregulated, resulting in decreased tumor growth in vitro and in vivo. Mice with modest-temporary hyperglycemia, induced by low-dose short-exposure streptozotocin, display accelerated tumor growth and lapatinib resistance, whereas combining lapatinib with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S42 phenylglycine t-butyl ester (DAPT) ameliorates tumor growth under these modest hyperglycemic conditions by inhibiting NOTCH and EGFR superfamilies. NOTCH activity is correlated withNRG1levels, and highNRG1levels predicts poor outcomes, particularly in HER2-positive breast cancer patients. Our findings highlight the hyperglycemia-linked epigenetic modulation ofNRG1as a potential therapeutic strategy for treating breast cancer patients with diabetes.