c-Myb interferes with inflammatory IL1α-NF-κB pathway in breast cancer cells

The transcription factor c-Myb can be involved in the activation of many genes with protumorigenic function; however, its role in breast cancer (BC) development is still under discussion. c-Myb is considered as a tumor-promoting factor in the early phases of BC, on the other hand, its expression in BC patients relates to a good prognosis. Previously, we have shown that c-Myb controls the capacity of BC cells to form spontaneous lung metastasis. Reduced seeding of BC cells to the lungs is linked to high expression of c-Myb and a decline in expression of a specific set of inflammatory genes. Here, we unraveled a c-Myb-IL1 alpha-NF-kappa B signaling axis that takes place in tumor cells. We report that an overexpression of c-Myb interfered with the activity of NF-kappa B in several BC cell lines. We identified IL1 alpha to be essential for this interference since it was abrogated in the IL1 alpha-deficient cells. Overexpression of IL1 alpha, as well as addition of recombinant IL1 alpha protein, activated NF-kappa B signaling and restored expression of the inflammatory signature genes suppressed by c-Myb. The endogenous levels of c-Myb negatively correlated with IL1 alpha on both transcriptional and protein levels across BC cell lines. We concluded that inhibition of IL1 alpha expression by c-Myb reduces NF-kappa B activity and disconnects the inflammatory circuit, a potentially targetable mechanism to mimic the antimetastatic effect of c-Myb with therapeutic perspective.

Automated summary

c-Myb is involved in the activation of genes with protumorigenic function, and its interaction with IL1 alpha and NF-kappa B signaling axis in tumor cells plays a critical role in regulating metastasis and inflammatory genes in breast cancer. This pathway presents a potential target for therapeutic interventions to mimic the antimetastatic effect of c-Myb.