Generation of Model Systems for the Study of Novel Cell Cycle Regulation in Development: Implications for Spy1 in Tumour Susceptibility

Cell cycle regulation lies at the heart of all developmental decisions, and aberrant regulation represents an important step in the onset of tumourigenesis. Alterations in cell cycle regulators are known to play a critical role in promoting tumour formation in a wide variety of tissues. The cyclin-like protein Spy1 is capable of binding and activating CDK2 and promoting progression through G1/S phase of the cell cycle. Spy1 can also target the cell cycle inhibitor p27 for degradation, and it has been shown to override cellular checkpoints and apoptotic pathways in response to DNA damage leading to enhanced cell survival. Previous data has shown that Spy1 levels are tightly regulated throughout mammary gland development, and high levels are associated with breast cancer, as well as cancer of the brain and liver. This suggests a role for Spy1 in normal mammary development as well as in the development of tumourigenesis. Transgenic and gene targeted models represent an ideal system in which to study altered protein expression on development and tumour initiation. This work describes the development of three novel model systems to study altered Spy1 expression on normal and abnormal development of the mammary gland. Using the newly generated MMTV-Spy1 mouse we have demonstrated that elevated levels of Spy1 increases mammary tumour susceptibility, and interestingly liver tumour susceptibility. We demonstrate that levels of Spy1 are downregulated in the event of DNA damage and the tumour suppressor p53 may be responsible for mediating this event. If p53 is unable to keep levels of Spy1 in check this can lead to uncontrolled cell proliferation, a hallmark of oncogenesis, and may contribute to tumour initiation. Thus for the first time, we demonstrate a role for Spy1 in mediating tumour susceptibility, highlighting the importance of maintaining proper checkpoint responses. Our work demonstrates that Spy1 could prove to be an attractive diagnostic marker and therapeutic target in the treatment of various forms of cancer, helping to eradicate this deadly disease