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.

• Keywords
• Breast cancer, IL1α, Inflammation, NF-κB, Transactivation, c-Myb,
• MeSH
• Epithelial-Mesenchymal Transition MeSH
• Interleukin-1alpha metabolism   MeSH
• Humans MeSH
• Inflammation Mediators metabolism   MeSH
• Biomarkers, Tumor metabolism   MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms etiology   metabolism   pathology   MeSH
• NF-kappa B metabolism   MeSH
• Proto-Oncogene Proteins c-myb metabolism   MeSH
• Amino Acid Sequence MeSH
• Signal Transduction * MeSH
• Endoplasmic Reticulum Stress MeSH
• Inflammation genetics   metabolism   pathology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• IL1A protein, human MeSH Browser
• Interleukin-1alpha MeSH
• Inflammation Mediators MeSH
• MYB protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• NF-kappa B MeSH
• Proto-Oncogene Proteins c-myb MeSH

BACKGROUND: The c-Myb transcription factor is essential for the maintenance of stem-progenitor cells in bone marrow, colon epithelia, and neurogenic niches. c-Myb malfunction contributes to several types of malignancies including breast cancer. However, the function of c-Myb in the metastatic spread of breast tumors remains unexplored. In this study, we report a novel role of c-Myb in the control of specific proteases that regulate the matrix-dependent invasion of breast cancer cells. RESULTS: Ectopically expressed c-Myb enhanced migration and ability of human MDA-MB-231 and mouse 4T1 mammary cancer cells to invade Matrigel but not the collagen I matrix in vitro. c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. The gene coding for cathepsin D was suggested as the c-Myb-responsive gene and downstream effector of the migration-promoting function of c-Myb. Finally, we demonstrated that c-Myb delayed the growth of mammary tumors in BALB/c mice and affected the metastatic potential of breast cancer cells in an organ-specific manner. CONCLUSIONS: This study identified c-Myb as a matrix-dependent regulator of invasive behavior of breast cancer cells.

• MeSH
• Electrophoresis, Polyacrylamide Gel MeSH
• Immunoblotting MeSH
• Cathepsin D genetics   metabolism   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Humans MeSH
• RNA, Small Interfering MeSH
• Matrix Metalloproteinase 1 genetics   metabolism   MeSH
• Matrix Metalloproteinase 9 genetics   metabolism   MeSH
• Neoplasm Metastasis genetics   physiopathology   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms genetics   metabolism   MeSH
• Cell Movement genetics   physiology   MeSH
• Proto-Oncogene Proteins c-myb genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cathepsin D MeSH
• RNA, Small Interfering MeSH
• Matrix Metalloproteinase 1 MeSH
• Matrix Metalloproteinase 9 MeSH
• Proto-Oncogene Proteins c-myb MeSH