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Rate-limiting Effects of Cyclin D1 in Transformation by ErbB2 Predicts Synergy between Herceptin and Flavopiridol¹

Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129 [R. N., E. V. S.]; Department of Surgery, Dana-Farber Cancer Institute, Boston, Massachusetts [J. D. I.]; Haematologikum der GSF, Institute for Clinical Molecular Biology and Tumor Genetics, Munich; Germany [B. K.]; and The Pediatric Service, Massachusetts General Hospital, Boston, Massachusetts 02114 [E. V. S.]

Cyclin D1 is downstream of erbB2 and is required for erbB2 transformation. Here we report thatcyclin D1 functions are essential, rate limiting for erbB2 transformation, and reciprocally increase erbB2 levels. This interaction depends on three cyclin D1 activities: cyclin-dependent kinase 4-dependent kinase activity, titration of p27, and an intrinsic transcriptional activity of cyclin D1. Drugs active against erbB2 and cyclin D1 (Herceptin and flavopiridol) were synergistically cytotoxic against erbB2-positive breast cancer cell lines. Addition of flavopiridol to Herceptin synergistically lowered erbB2 levels in these cells. Our data suggest the potential use of combinations of cyclin-dependent kinase inhibitors and Herceptin in breast cancer.

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