Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression. (1st March 2021) - Kim, Su-Jung
Abstract: Persistent activation of STAT3 and Nrf2 is considered to stimulate the aggressive behavior of basal-like breast cancer (BLBC). However, the precise mechanism underlying sustained overactivation of these transcription factors and their roles in breast cancer progression remain elusive. Analysis of the TCGA multi-omics data showed that high levels of STAT3 and Nrf2 mRNA were correlated with elevated expression of P-STAT3 Y705 and Nrf2 target proteins in breast cancer patients. Our present study demonstrates a unique interaction between Nrf2 and STAT3 in the maintenance and progression of BLBC. RNA sequencing analysis identified the gene encoding IL-23A upregulated by concurrent binding of STAT3 and Nrf2 to its promoter. IL-23A depletion also showed the similar phenotypic changes to those caused by double knockdown of both transcription factors. In conclusion, the STAT3-Nrf2 interaction accelerates BLBC growth and progression by augmenting IL-23A expression, which underscores the importance of subtype-specific molecular pathways in human breast cancer. Highlights: Tumors from breast cancer patients exhibit high co-expression of P-STAT3 Y705 and Nrf2. Nrf2 and STAT3 physically interact, and the complex was detected predominantly in nucleus. The Nrf2 and STAT3 complex enhances IL-23A expression by binding to its promoter.