BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment

Abstract

Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling. The pathways by which tumor cells evade immune surveillance, immune therapies, and take advantage of antitumor immunity are poorly understood, but likely depend on metabolic inflammation in the microenvironment. Immune functions are abnormal in metabolic disease, and lessons learned from preclinical studies in lean and metabolically normal environments may not translate to patients with obesity and metabolic disease. This problem is made more urgent by the rising incidence of breast cancer among women who are not obese but who have metabolic disease and associated inflammation, a phenotype common in Asia. The somatic BET proteins, comprising BRD2, BRD3, and BRD4, are new critical regulators of metabolism, coactivate transcription of genes that encode proinflammatory cytokines in immune cell subsets infiltrating the microenvironment, and could be important targets in breast cancer immunotherapy. These transcriptional coregulators are well known to regulate tumor cell progression, but only recently identified as critical for metabolism, metastasis, and expression of immune checkpoint molecules. We consider interrelationships among metabolism, inflammation, and breast cancer aggressiveness relevant to the emerging threat of breast cancer among women with metabolic disease, but without obesity.

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

“…As a chronic disease, T2D may cause inflammatory response in different organs or tissues (34). Increasing studies report the critical role of BRD4 in the regulation of inflammatory response, suggesting that BRD4 might be implicated in the pathology of diabetes (35,36).…”

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

“…BETs inhibition was initially shown to be highly effective in blocking transcription programs of inflammation 28 and oncogenic proliferation 29 . The importance of BET biology was then extended to stem cell differentiation, hematopoiesis, synaptic plasticity 12 , and recently, also adipogenesis 10,30 . Most recently, BRD4 was found to regulate intra-nuclear/cellular processes as well, such as chromatin architectural remodeling 31 and autophagy 11 .…”

“…BRD4 has been shown to play a master role in broad cellular processes ranging from proliferation to differentiation 10 to autophagy 11 . Curiously, whether BETs are directly involved in cholesterol homeostasis remained unclear 12 . Relevant to this question, recent studies identified a crucial role of BRD4 in adipogenesis 10 .…”

Emerging roles of and therapeutic strategies targeting BRD4 in cancer

“…Collectively, the molecular signaling events that occur within the TME function to promote tumor progression and enable cancer cells to acquire phenotypic properties such as enhanced invasion and migration that are critical to the development of cancer metastasis. In support of this, recent data suggests a direct role for BRD4 in the epigenetic regulation of gene expression in both cancer cells and non-neoplastic cells present in the TME that promotes tumorigenesis [15, 34]. …”

“…Jagged1 is a Notch ligand and upon binding of Jagged1 to the Notch receptor, Notch is cleaved and translocates to the nucleus where it binds to CBF1, Suppressor of Hairless, Lag-1 (CSL) and Coenzyme A (CoAs) and activates the expression of transcription factors that are vital in EMT, such as Snail and Slug [32]. Studies have shown that BRD4 promotes the migratory properties of breast cancer cell lines through Notch1-induced signaling [15, 33]. Interestingly, studies have demonstrated that the pro-inflammatory cytokine IL-6 increases BRD4 enrichment at the proximal portion of the Jagged1 promoter region, supporting the idea that tumor-associated inflammatory mediators may alter the epigenetic ‘reading’ functions of BRD4 in cancer cells.…”