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.

Keywords: BET proteins; Type 2 diabetes; breast cancer; chronic inflammation; metabolic disease.

Figure 1.. Cellular crosstalk in the breast tumor microenvironment.

Tumor cells engage in paracrine signal transduction networks with nearby white adipocytes and pro-inflammatory T cell subsets that infiltrate the adipose tissue depot. The functions of these non-tumor cell types are highly abnormal in T2D and likely drive tumor progression. BET bromodomain proteins regulate tumor cell proliferation, invasiveness, migration and metastatic potential in response to these signals from the microenvironment cells, as well as immune exhaustion markers (e.g., PD-L1) that are elevated in metabolic inflammation. These non-tumor cells both upregulate immune exhaustion markers on lymphocytes (e.g., PD-1) in response to metabolic inflammation [144], and produce cytokines, under the control of the same subset of BET bromodomain proteins. Therefore, small molecule inhibitors that selectively ablate production of pro-metastatic factors could reduce the risks for tumor progression, improve immune exhaustion in metabolic disease and ‘cure’ the microenvironment, as well as reduce tumor proliferation and cell-intrinsic metastatic programs like EMT.

Figure 2.. BET proteins function as co-activators or co-repressors, depending on the cell type and signaling context.

Small molecule BET inhibitors (BETi) or shRNA against individual BET proteins perturb both transcriptional co-activation and co-repression processes. Cell proliferation, inflammation and immune exhaustion genes are positively regulated by the three BET proteins, thus inhibition or knockdown reduces their expression. However, certain other genes are activated upon BETi treatment or shRNA knockdown, including the insulin gene and targets of PPARγ. Small molecule approaches must therefore be sufficiently selective to carefully avoid undesirable on-target effects in nearby non-tumor cells of the microenvironment or elsewhere in the patient [53]. Ac: acetyl groups, Pol II: RNA Polymerase II, TAF: TATA-binding protein associated factor.