Our work has shown that the transcription factor Myb/MYB is essential to maintain stem/progenitor cell homeostasis in epithelium of the skin, mammary gland and the intestines. Myb is over-expressed in most breast and colorectal cancer (CRC). Indeed, Myb is a poor prognosis marker in CRC and patients among whom the ones with highest Myb are most likely to relapse. Thus we have investigated the molecular basis for why abnormally high Myb is such a poor prognosis indicator.
To mimic CRC patients with increased Myb activity, we generated the first intestinal-specific, inducible transgenic model for Myb and activated Myb during CRC initiation using a pro-carcinogen treatment, azoxymethane. As a result of Myb activation most measured aspects of colon stem cell gene expression and function were exacerbated and tumorigenesis was accelerated. CRC-associated symptoms of patients including intestinal bleeding and anemia were faithfully mimicked in our transgenic model identifying an additional pathogenic role for Myb. Further experiments using a syngeneic tumour mouse model with enforced Myb expression in CRC cells also identified a new immunomodulatory function of Myb in CRC.
Our work suggests that Myb has a driver role in CRC and provides clues to unravel the many faces of Myb in cancer to understand why patients with low Myb expression do better than those with high Myb expression.