The Interaction between Macrophages and Triple-negative Breast Cancer Cells Induces ROS-Mediated Interleukin 1 alpha Expression to Enhance Tumorigenesis and Metastasis

Triple-negative breast cancer (TNBC) has higher mortality than non-TNBC because of its stronger metastatic capacity. Increasing studies reported that TNBC tumors had more macrophage infiltration than non-TNBC tumors, which promoted the metastasis of TNBC cells. However, how TNBC cells become more malignant after interacting with macrophages is less reported. In this study, it is observed that when TNBC cells are co-cultured with macrophages, they display higher viability and stronger metastatic ability than non-TNBC cells. Mechanistic studies reveal that TNBC cells acquired these abilities via interactions with macrophages in three phases. First, within 12 h of co-culture with macrophages, some TNBC cells have significantly elevated levels of reactive oxygen species (ROS), which upregulate interleukin 1 alpha (IL1 alpha) expression in ERK1/2-c-Jun- and NF-kappa B-dependent manners at 24-48 h. Second, the secreted IL1.. bound to IL1R1 activates the ERK1/2-ZEB1-VIM pathway which increases metastasis. Third, IL1 alpha/IL1R1 facilitates its own synthesis and induces the expression of IL1 beta and IL8 at 72-96 h through the MKK4-JNK-c-Jun and NF-kappa B signaling pathways. Moreover, a higher level of IL1 alpha is positively correlated with more macrophage infiltration and shorter overall survival in breast cancer patients. Thus, reducing ROS elevation or downregulating IL1 alpha expression can serve as new strategies to decrease metastasis of TNBC.

Automated summary

Triple-negative breast cancer (TNBC) has a higher mortality rate due to its strong metastatic capacity. Studies have shown that TNBC tumors have more infiltration of macrophages, which contributes to TNBC cell metastasis. However, the mechanisms behind how TNBC cells become more malignant after interacting with macrophages are not well understood. This study demonstrates that TNBC cells co-cultured with macrophages exhibit increased viability and metastatic ability compared to non-TNBC cells. Mechanistic studies reveal that this is attributed to the interaction of TNBC cells with macrophages in three phases, involving elevated levels of reactive oxygen species (ROS), upregulation of interleukin 1 alpha (IL1 alpha) expression, and activation of signaling pathways. Additionally, higher levels of IL1 alpha are associated with more macrophage infiltration and shorter overall survival in breast cancer patients. Therefore, targeting ROS or downregulating IL1 alpha expression may serve as potential strategies to reduce TNBC metastasis.