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.

Public Health Relevance

There is no effective treatment for women of African descent (WAD) who suffer most often from the deadly triple negative (TN) form of breast cancer (BrCa). We have found a genetic variant of the IRAK-4 kinase that occurs 5X more frequently among WAD with BrCa. IRAK-4 regulates immune responses from both tumor cells and circulating immune cells. We will test whether inhibiting IRAK-4 in BrCa tumors or in immune cells of maturing zebrafish or in both together can slow down or eliminate BrCa progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA185361-01
Application #
8687178
Study Section
Special Emphasis Panel (ZRG1-OBT-Z (55))
Program Officer
Wali, Anil
Project Start
2014-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$187,811
Indirect Cost
$57,311
Name
North Carolina Central University
Department
None
Type
Organized Research Units
DUNS #
783691801
City
Durham
State
NC
Country
United States
Zip Code
27707