The Role of IRAK-4 in African American Breast Cancer

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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.