FOXM1 is a potent oncogenic transcription factor that plays essential roles in multiple hallmarks of cancer progression, thus having impacts on tumour initiation, invasion, angiogenesis, cancer stemness and drug sensitivity. Likewise, high mobility group proteins, HMGA1 and HMGN1 are also involved in tumorigenic and metastatic processes in cancer. The human protein-protein interactions prediction database has reported the potential interactions between these proteins, but no further experimental evidence to confirm and characterise this link. In my project, I demonstrated that FOXM1 binds to HMGA1 or HMGN1 as protein-protein complex, and such interactions affect the transcriptional regulation of KIF20A and SQSTM1/p62. Disruption of the complex or their protein expression levels significantly affects drug sensitivity, cell migration and invasion in breast cancer cells. Apart from the essential roles of HMGA1 and HMGN1 in DNA repair mechanisms, they influence these malignant processes may partially through regulating FOXM1 activities. Thus, the functions of these FOXM1’s transcriptional targets, KIF20A and p62 were further examined. The results showed the p62 is involved in modulating angiogenic and metastatic processes in breast cancer as silencing of p62 significantly attenuated tumour-induced angiogenesis and cell migration in zebrafish. Furthermore, KIF20A is a novel target which KIF20A inhibition increased drug sensitivity and reduced cell migration, invasion and mammosphere formation. In addition, the new KIF20A inhibitor, BKS0349 compound offers a viable therapeutic option for cancer treatment in future.
In summary, my results have established a potential mechanism underlying the interactions between FOXM1, HMGA1 and HMGN1 in breast cancer cells. Collectively, these findings strengthen our current understanding of the oncogenic protein FOXM1-mediated cancer progression and provide new insights into cancer diagnosis and treatment.