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Loss of epigenetic regulation disrupts lineage commitment and promotes breast cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE178424 | GEO | 2022/09/12

REPOSITORIES: GEO

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Loss of epigenetic regulation disrupts lineage commitment and promotes breast cancer (scRNA-Seq)

Project description:Systematically investigating the scores of genes mutated in cancer to discern the real drivers from the inconsequential bystanders is a prerequisite for Precision Medicine but remains challenging. Here, we use CRISPR/Cas9-mediated somatic gene editing in a breast cancer mouse model to assess the transforming potential of 215 recurrent ‘long-tail’ breast cancer genes. Several core and accessory components of the COMPASS-like histone methylase complex, namely KMT2C, KDM6A and ASXL2 cooperated with PIK3CAH1047R mutation to accelerate mammary tumorigenesis in mice and to transform human breast epithelial cells. Mechanistically, mutations of these ‘EpiDrivers’ converged on enhancing the lineage conversion of basal cells to luminal cells prior to tumorigenesis, as well as an aberrant alveolar differentiation program in both luminal and basal cells. Overall, our work suggests that lactation mimicry is associated with the earliest steps of breast cancer.

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Loss of epigenetic regulation disrupts lineage commitment and promotes breast cancer

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

Project description:Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression remain poorly understood. Here, we show that hyperglycemia causes active histone modifications at the Nrg1 enhancer, 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-controlled Nrg1 levels 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 with NRG1 levels, and high NRG1 levels predicts poor outcomes, particularly in HER2-positive breast cancer patients. Our findings highlight the hyperglycemia-linked epigenetic modulation of NRG1 as a potential therapeutic strategy for treating breast cancer patients with diabetes.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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