Consequence of the tumor‐associated conversion to cyclin D1b

Abstract

Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non‐redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b‐driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre‐clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant.SynopsisNovel murine models were generated that mimic tumour‐associated conversion to cyclin D1b and novel links uncovered between cyclin D1b expression and high PARP activity and genome instability markers, which could be exploited to inhibit tumour growth.Novel murine models were generated that mimic the tumor‐associated conversion to cyclin D1b.Induction of cyclin D1b phenocopies some but not all phenotypes observed upon cyclin D1 loss.Unlike cells expressing full‐length cyclin D1, cells expressing endogenous cyclin D1b undergo transformation, thus demonstrating the unique transforming capacity of this cyclin D1 variant.Cyclin D1b induces evidence of DNA damage and promotes PARP1 activity, linking the DNA damage pathway to cyclin D1b‐mediated oncogenic events.Novel means to suppress growth of cyclin D1b‐positive tumor cells were identified, providing the first preclinical insight into means by which to target tumors reliant on cyclin D1b expression.Novel murine models were generated that mimic tumour‐associated conversion to cyclin D1b and novel links uncovered between cyclin D1b expression and high PARP activity and genome instability markers, which could be exploited to inhibit tumour growth.