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

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2021-03, Vol.23 (3), p.326-336
• Main Authors: Dúcka, Monika, Kučeríková, Martina, Trčka, Filip, Červinka, Jakub, Biglieri, Elisabetta, Šmarda, Jan, Borsig, Lubor, Beneš, Petr, Knopfová, Lucia
• Format: Article
• Language: English
• Subjects: Breast cancer; c-Myb; IL1α; Inflammation; NF-κB; Original Research; Transactivation
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2021.01.002

•c-Myb attenuates NF-κB activity in breast cancer.•Interaction with co-activator p300 is required for NF-κB suppression by c-Myb.•c-Myb negatively regulates IL1a transcription in several ER- breast cancer cell lines.•Inhibition of IL1α expression mediates the anti-inflammatory effect of c-Myb. 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-IL1α-NF-κB signaling axis that takes place in tumor cells. We report that an overexpression of c-Myb interfered with the activity of NF-κB in several BC cell lines. We identified IL1α to be essential for this interference since it was abrogated in the IL1α-deficient cells. Overexpression of IL1α, as well as addition of recombinant IL1α protein, activated NF-κB signaling and restored expression of the inflammatory signature genes suppressed by c-Myb. The endogenous levels of c-Myb negatively correlated with IL1α on both transcriptional and protein levels across BC cell lines. We concluded that inhibition of IL1α expression by c-Myb reduces NF-κB activity and disconnects the inflammatory circuit, a potentially targetable mechanism to mimic the antimetastatic effect of c-Myb with therapeutic perspective.