BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment.
BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment.
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DOI：
10.1002/jlb.5ri0917-380rr
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发表时间：
2018-08
影响因子：
5.5
通讯作者：
Denis GV
中科院分区：
文献类型：
--
作者：
Andrieu GP;Shafran JS;Deeney JT;Bharadwaj KR;Rangarajan A;Denis GV
肥胖及其相关病理2型糖尿病是两种慢性代谢性和炎症性疾病，可促进乳腺癌进展、转移和不良结局。新出现的批评意见认为未解决的炎症和代谢异常与肥胖分开;它们不同时发生的环境可以告知疾病机制。在乳腺癌中，肿瘤微环境通常被通过代谢信号编程的T效应细胞和T调节细胞浸润。肿瘤细胞逃避免疫监视、免疫治疗和利用抗肿瘤免疫的途径知之甚少，但可能依赖于微环境中的代谢炎症。代谢性疾病的免疫功能是异常的，从精益和代谢正常环境中的临床前研究中吸取的教训可能不会转化为肥胖和代谢性疾病患者。由于不肥胖但患有代谢疾病和相关炎症（这是亚洲常见的表型）的女性乳腺癌发病率不断上升，这一问题变得更加紧迫。BET蛋白，包括BRD 2、BRD 3和BRD 4，是新的代谢关键调节剂，共激活浸润微环境的免疫细胞亚群中编码促炎细胞因子的基因的转录，并且可能是乳腺癌免疫治疗中的重要靶点。众所周知，这些转录辅助调节因子调节肿瘤细胞的进展，但最近才被确定为对代谢、转移和免疫检查点分子的表达至关重要。我们认为代谢、炎症和乳腺癌侵袭性之间的相互关系与患有代谢疾病但没有肥胖的女性中乳腺癌的新威胁有关。2型糖尿病是乳腺癌进展的一个未充分研究的因素; BET蛋白引起的疾病相关慢性炎症是肿瘤微环境的危险修饰剂。
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 anti-tumor immunity are poorly understood, but likely depend on metabolic inflammation in the microenvironment. Immune functions are abnormal in metabolic disease, and lessons learned from pre-clinical 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 BET proteins, comprising BRD2, BRD3 and BRD4, are new critical regulators of metabolism, co-activate transcription of genes that encode pro-inflammatory cytokines in immune cell subsets infiltrating the microenvironment, and could be important targets in breast cancer immunotherapy. These transcriptional co-regulators 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. Type 2 diabetes is an understudied contributor to progression of breast cancer; disease-associated chronic inflammation by BET proteins is a dangerous modifier of tumor microenvironments.