RT Journal Article
SR Electronic
T1 The Atypical Cyclin-Like Protein Spy1 Overrides p53-Mediated Tumour Suppression and Promotes Susceptibility to Breast Tumorigenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 535310
DO 10.1101/535310
A1 Bre-Anne Fifield
A1 Ingrid Qemo
A1 Evie Kirou
A1 Robert D. Cardiff
A1 Lisa Ann Porter
YR 2019
UL http://biorxiv.org/content/early/2019/07/18/535310.abstract
AB Background Breast cancer is the most common cancer to affect women and one of the leading causes of cancer related deaths. Proper regulation of cell cycle checkpoints plays a critical role in preventing the accumulation of deleterious mutations. Perturbations in the expression or activity of mediators of cell cycle progression or checkpoint activation represent important events that may increase susceptibility to the onset of carcinogenesis. The atypical cyclin-like protein Spy1 was isolated in a screen for novel genes that could bypass the DNA damage response. Clinical data demonstrates that protein levels of Spy1 are significantly elevated in ductal and lobular carcinoma of the breast. We hypothesized that elevated Spy1 would override protective cell cycle checkpoints and support the onset of mammary tumorigenesis.Methods We generated a transgenic mouse model driving expression of Spy1 in the mammary epithelium. Mammary development, growth characteristics and susceptibility to tumorigenesis was studied. In vitro studies were conducted to investigate the relationship between Spy1 and p53.Results We found that in the presence of wild-type p53, Spy1 protein is held ‘in check’ via protein degradation, representing a novel endogenous mechanism to ensure protected checkpoint control. Regulation of Spy1 by p53 is at the protein level and is mediated in part by Nedd4. Mutation or abrogation of p53 is sufficient to allow for accumulation of Spy1 levels resulting in mammary hyperplasia. Sustained elevation of Spy1 results in elevated proliferation of the mammary gland and susceptibility to tumorigenesis.Conclusions This mouse model demonstrates for the first time that degradation of the cyclin-like protein Spy1 is an essential component of p53-mediated tumour suppression. Targeting cyclin-like protein activity may therefore represent a mechanism of resensitizing cells to important cell cycle checkpoints in a therapeutic setting.