Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
Expert Rev Mol Med. 2023 Jun 20;25:e22. doi: 10.1017/erm.2023.14.
Inflammation and immune evasion are major key players in breast cancer (BC) progression. Recently, the FDA approved the use of anti-programmed death-ligand 1 antibody (anti-PD-L1) and phosphoinositide 3-kinase (PI3K) inhibitors against aggressive BC. Despite the paradigm shift in BC treatments, patients still suffer from resistance, recurrence and serious immune-related adverse events. These obstacles require unravelling of the hidden molecular contributors for such therapy failure hence yielding therapeutics that are at least as efficient yet safer. Inflammasome pathway is activated when the pattern recognition receptor senses danger signals (danger-associated molecular patterns) from damagedRdying cells or pathogen-associated molecular patterns found in microbes, leading to secretion of the active pro-inflammatory cytokines interleukin-1 (IL-1) and interleukin-18 (IL-18). It has been shown throughout numerous studies that inflammasome pathway enhanced invasion, metastasis, provoked BC progression and therapy resistance. Additionally, inflammasomes upregulated the proliferative index ki67 and enhanced PD-L1 expression leading to immunotherapy resistance. IL-1 contributed to significant decrease in oestrogen receptor levels and promoted BC chemo-resistance. High levels of IL-18 in sera of BC patients were associated with worst prognosis. Stimulation of purinergic receptors and modulation of adipokines in obese subjects activated inflammasomes that evoked radiotherapy resistance and BC progression. The micro RNA miR-223-3p attenuated the inflammasome over-expression leading to lowered tumour volume and lessened angiogenesis in BC. This review sheds the light on the molecular pathways of inflammasomes and their impacts in distinct BC subtypes. In addition, it highlights novel strategies in treatment and prevention of BC.
炎症和免疫逃逸是乳腺癌（BC）进展的主要关键因素。最近，FDA 批准了抗程序性死亡配体 1 抗体（抗 PD-L1）和磷酸肌醇 3-激酶（PI3K）抑制剂用于治疗侵袭性 BC。尽管 BC 治疗方法发生了范式转变，但患者仍面临耐药性、复发和严重的免疫相关不良事件。这些障碍需要揭示导致这种治疗失败的隐藏分子因素，从而产生至少同样有效但更安全的治疗方法。炎症小体途径在模式识别受体感知到受损/垂死细胞的危险信号（危险相关分子模式）或微生物中存在的病原体相关分子模式时被激活，导致活性促炎细胞因子白细胞介素 1（IL-1）和白细胞介素 18（IL-18）的分泌。大量研究表明，炎症小体途径增强了侵袭、转移，引发了 BC 的进展和治疗耐药性。此外，炎症小体上调了增殖指数 ki67 并增强了 PD-L1 的表达，导致免疫治疗耐药性。IL-1 导致雌激素受体水平显著下降，并促进了 BC 的化疗耐药性。BC 患者血清中高水平的 IL-18 与预后最差相关。嘌呤能受体的刺激和肥胖患者脂肪因子的调节激活了炎症小体，导致放射治疗耐药性和 BC 进展。微 RNA miR-223-3p 减弱了炎症小体的过度表达，导致肿瘤体积减小和血管生成减少。这篇综述阐明了炎症小体的分子途径及其在不同 BC 亚型中的影响。此外，它还强调了 BC 治疗和预防的新策略。
