Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer

D-type cyclins are important cell cycle regulators that promote cellular pr oliferation in response to growth factors by inactivation of the retinoblas toma protein (Rb), Cyclin D1 has been shown to be overexpressed in several cancer types and to act as an oncogene in breast cancers. As D-type cyclins are rate limiting for progression into S phase, the level at which they ac cumulate must be carefully regulated. Several mechanisms leading to overexp ression of cyclin D1 have been reported including amplification, translocat ion and stabilization of the mRNA, Here, we present data showing elevated c yclin D1 protein in breast cancer samples in the absence of elevated mRNA l evel. Further, we found that in these cases, cyclin D3 protein also accumul ates and that the coordinate increase in cyclin D1 and D3 occurs in 15% (7/ 47) of breast cancers. In addition we show that blocking the activity of th e 26S proteosome results in the accumulation of cyclin D1 and D3, that both D-type cyclins are abiquitinated and associate with Cul-1, a component of the SCF ubiquitin Ligase complex. Finally, we show that the coordinated ele vation of cyclin D1 and D3 is also observed in the breast cell line MCF-7 a nd demonstrate that the degradation of cyclin D1 and D3 is deficient in thi s cell line. These results indicate that cyclin D1 and cyclin D3 share a co mmon mechanism of degradation and we propose that the coordinate increase o f D-type cyclins observed in primary breast cancers reflects a defect in th eir proteolysis.