Summary Cyclin D1 is frequently overexpressed in breast cancer but surprisingly it correlates with improved breast cancer survival compared to non-overexpressing breast cancers. The reason underlying this unexpected effect remains unknown. We show here that cyclin D1 overexpression represses the expression of the anti-apoptotic transcription factor STAT3 and confirmed this negative correlation in 286 human cancer samples. We also show that stabilization of cyclin D1, using the proteasome inhibitor bortezomib, further amplifies the cyclin D1-dependent repression of STAT3 and of its transcriptional target Bcl-XL. In addition, as bortezomib treatment induces apoptosis but is limited by Bcl-XL, cyclin D1 overexpression sensitizes breast cancer cells to bortezomib. The resulting feedback loop specifically induces the death of cyclin D1 overexpressing cells. Significance Oncogenes such as Myc are known to activate apoptosis but inactivation of the Arf-Mdm2-p53 pathway in most cancers blocks this effect. Cyclin D1 repression of STAT3 represents a novel pathway for the activation of apoptosis following oncogenic activation and offers a potential mechanism for the beneficial effect of cyclin D1 overexpression on breast cancer survival. In addition, we identified bortezomib as a drug able to amplify the pro-apoptotic function of cyclin D1. As bortezomib is currently tested in several clinical trials, these results might provide a new approach to identify patients cohort, which will most benefit from bortezomib treatment. Cyclin D1 level may therefore represent a marker for predicting the response to this novel anti-cancer drug.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]