Interleukin-1 Receptor-Associated Kinase 1 in Cancer Metastasis and Therapeutic Resistance: Mechanistic Insights and Translational Advances.

Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is a serine/threonine kinase that plays a critical role as a signaling transducer of the activated Toll-like receptor (TLR)/Interleukin-1 receptor (IL-1R) signaling pathway in both immune cells and cancer cells. Upon hyperphosphorylation by IRAK4, IRAK1 forms a complex with TRAF6, which results in the eventual activation of the NF-κB and MAPK pathways. IRAK1 can translocate to the nucleus where it phosphorylates STAT3 transcription factor, leading to enhanced IL-10 gene expression. In immune cells, activated IRAK1 coordinates innate immunity against pathogens and mediates inflammatory responses. In cancer cells, IRAK1 is frequently activated, and the activation is linked to the progression and therapeutic resistance of various types of cancers. Consequently, IRAK1 is considered a promising cancer drug target and IRAK1 inhibitors have been developed and evaluated preclinically and clinically. This is a comprehensive review that summarizes the roles of IRAK1 in regulating metastasis-related signaling pathways of importance to cancer cell proliferation, cancer stem cells, and dissemination. This review also covers the significance of IRAK1 in mediating cancer resistance to therapy and the underlying molecular mechanisms, including the evasion of apoptosis and maintenance of an inflammatory tumor microenvironment. Finally, we provide timely updates on the development of IRAK1-targeted therapy for human cancers.

Crosstalk between breast cancer-derived microRNAs and brain microenvironmental cells in breast cancer brain metastasis.

Breast cancer is the most frequent malignancy in women, constituting 15.2% of all new cancers diagnosed in the United States. Distant breast cancer metastasis accounts for the majority of breast cancer-related deaths; brain metastasis is the third most common site for metastatic breast cancer but is associated with worst prognosis of approximately eight months of survival. Current treatment options for breast cancer brain metastasis (BCBM) are limited and ineffective. To help identify new and effective therapies for BCBM, it is important to investigate the mechanisms by which breast cancer cells metastasize to the brain and thrive in the brain microenvironment. To this end, studies have reported that primary breast tumor cells can prime brain microenvironmental cells, including, astrocytes and microglia, to promote the formation of BCBM through the release of extracellular vesicle-microRNAs (miRNAs). Breast tumor-derived miRNAs can also promote breast cancer cell invasion through the blood-brain barrier by disrupting the integrity of the brain microvascular endothelial cells. In this review, we summarize current literature on breast cancer-derived BCBM-promoting miRNAs, cover their roles in the complex steps of BCBM particularly their interactions with microenvironmental cells within the brain metastatic niche, and finally discuss their therapeutic applications in the management of BCBM.