The Role of IRAK-4 in African American Breast Cancer

描述(申请人提供)：迫切需要有针对性的治疗方法来治疗侵袭性形式的乳腺癌(BRCA)，包括在非洲裔妇女(WAD)中最常见的三阴性(TN)表型。参与乳腺上皮对病原体和损伤的“第一反应”的先天免疫标记物是很有希望的靶标。 基于越来越多的证据表明炎症和乳腺癌(BRCA)之间存在因果关系。最近的一项初步研究检查了在患有BRCA的WAD中选择的先天免疫基因中出现微小变异的情况，发现拥有IL-1受体相关激酶4(IRAK-4)变体的WAD患BRCA的可能性是对照组的5倍(Yeyeodu等人，提交)。IRAK-4是天然免疫和获得性免疫的调节蛋白，分别从Toll样受体(TLRs)、IL-1R家族和T细胞受体传递信号。实验和临床证据表明，天然免疫TLR的调节和过度表达对BRCA的进展既有负面影响，也有积极影响(Kidd等人，2013)，因此我们最近的发现表明，靶向多个TLR途径的下游调节因子IRAK-4可能是一种首选的方法。将使用1)携带IRAK-4变体的TN WAD细胞系，2)能够区分先天免疫和获得性免疫以及肿瘤和宿主IRAK-4表达的体内斑马鱼BRCA异种移植模型，以及3)商业上可获得的IRAK-4抑制剂来探索IRAK-4在wAD BRCA进展中的功能作用。这些战略工具将一起用于确定IRAK-4作为治疗TN BRCA的可行靶点的治疗潜力。

DESCRIPTION (provided by applicant): There is a desperate need for targeted therapies to treat aggressive forms of breast cancer (BrCa), including the triple negative (TN) phenotype that most frequently occurs among women of African descent (WAD). Innate immune markers, involved in the "first response" of breast epithelia to pathogens and injury, are promising targets based on mounting evidence that suggests a causal relationship between inflammation and breast cancer (BrCa). A recent pilot study examined the occurrence of minor variants in selected innate immune genes among WAD with BrCa and found that WAD possessing a variant of IL-1 receptor associated kinase 4 (IRAK- 4) were 5X more likely to have BrCa (Yeyeodu et al., submitted). IRAK-4 is a regulatory kinase in both innate and adaptive immunity, transducing signals from Toll-like receptors (TLRs) and from IL-1R family and T-cell receptors, respectively. Experimental and clinical evidence show that modulation and overexpression of innate immune TLRs have both a negative and positive impact on BrCa progression (Kidd et al., 2013), so our recent findings suggest that targeting IRAK-4, a downstream regulator of multiple TLR pathways, may be a preferred approach. The functional role of IRAK-4 in WAD BrCa progression will be explored using 1) a TN WAD cell line that carries the IRAK-4 variant, 2) an in vivo zebrafish BrCa xenograft model that can distinguish between innate and adaptive immunity and between tumor and host IRAK-4 expression and 3) a commercially available IRAK-4 inhibitor. Together these strategic tools will be used to determine the therapeutic potential of IRAK-4 as a viable target in the treatment of TN BrCa.