Kinase independent oncogenic cyclin D1

a driving force in breast cancer and many other types of human tumors. Cyclin D1 overexpression is found in up to 50% of human breast cancers, and the pattern of cyclin D1 overexpression in tissues along the spectrum from normal epithelium to invasive breast cancer suggests its involvement in the earliest stages of mammary carcinogenesis. The importance of cyclin D1 as a driver oncogene is reinforced by the frequent clonal selection of cyclin D1 gene amplification, found in 15-20% of breast cancers, associated with poor prognosis, and by the fact that tissue-specific overexpression of cyclin D1 in transgenic mice results in mammary hyperplasia and adenocarcinoma [1]. However, the precise mechanisms through which cyclin D1 overexpression contributes to breast tumorigenesis have been controversial. Specifically, while cyclin D1's role in the pathogenesis of breast cancer may well involve, at least in part, the well-established binding/activation of its catalytic partner kinases CDK4/6, with subsequent hyperphosphorylation of pRB and G1-S cell cycle transition, several lines of evidence have suggested that cyclin D1, especially when overexpressed in the setting of cancer, may also act through other, CDK-independent, mechanisms. These alternative mechanisms of cyclin D1 action carry tremendous potential significance, for example in the rational targeting of new therapeutic agents. Our recent study [2] is perhaps the most direct test of this hypothesis performed in a highly relevant in vivo model system. The induction of chromosomal instability is known to promote genetic rearrangements, tumorigenesis and the molecular genetic chaos associated with poor outcome cancers. The early drivers to chromosomal instability are poorly understood. Our recent studies showed that modest overexpression of cyclin D1 is sufficient for the induction of chromosomal instability within 3 cell divisions, both in vitro and in vivo. Furthermore we showed the induction of CIN occurred independently of the kinase function. In ChIP-Seq cyclin D1 associates with genes governing chromosomal instability (CIN) [3]. Using a kinase dead mutant of cyclin D1 (cyclin D1 KE) we showed cyclin D1 induced-mitotic spindle architecture changes of chromosomal instability and supernumerary centrosomes aneuploidy and other features of CIN. In cdk4/6-/-3T3 cells cyclin D1 WT and Editorial cyclin D1 KE induced aneuploidy to a similar degree compared to control cells. Cyclin D1 KE induced aneuploidy to a similar extent in absence or presence of cdk4/6 agonist. Crucially, sustained transgenic expression of cyclin D1 KE induced mammary adenocarcinoma with similar kinetics to that of a cyclin D1 WT transgene …