Investigating the role of the MYB-BUB1 axis in adenoid cystic carcinoma

Abstract

Adenoid cystic carcinoma (ACC) is a malignancy originating in salivary glands. Although more frequent in the head and neck region, ACC can also arise from exocrine glands in other body locations, such as breast, respiratory tract, and genitourinary system. ACC is slow growing but relentless, and poorly responding to chemotherapy or other therapeutic interventions, explaining the high frequency of recurrence, propensity to metastasise, and poor prognosis. Overexpression of the MYB transcription factor and oncoprotein is a hallmark of ACC; however, the inherent difficulty of pharmacological inhibition of transcription factors and the critical role of MYB in normal haematopoiesis have stalled the progression of direct targeting strategies. Another difficulty in ACC research is the lack of reliable, easy-to-use cellular models. In this PhD study, we have developed a new model of ACC by expressing a switchable MYB transgene in non-tumourigenic MCF10A breast epithelial cells. Upon MYB expression, the model recapitulated transcriptional features of ACC patient-derived gene expression profiles, affirming clinical relevance. Analysis of MYB-regulated genes at the global level identified the mitotic checkpoint kinase BUB1 as a potential therapeutic target. We found that BUB1 is directly regulated by MYB at the promoter level and co-expressed with MYB in ACC tumours. Pharmacological inhibition of BUB1 caused suppression of proliferation and apoptosis of primary ACC cells and impaired the growth of MYB-overexpressing, but not MYB-negative, MCF10A cells, indicating that the oncogene could be used as a biomarker of drug response in glandular tumours. Overall, these results suggest that newly designed ACC models could become valuable and versatile tools for research providing a cost-effective, reproducible alternative to patient-derived cell lines or xenotransplants. The MYB-BUB1 axis unveiled in this study using the novel cellular model of ACC has the potential to increase therapeutic opportunities for cancer patients.