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Tumors Initiated by Constitutive Cdk2 Activation Exhibit Transforming Growth Factor ß Resistance and Acquire Paracrine Mitogenic Stimulation during Progression

¹ Department of Pharmacology and Therapeutics and the Shands Cancer Center, University of Florida, Gainesville, Florida; ² Department of Cancer Biology and the Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and ³ Department of Pathology, Copenhagen University Hospital Herlev, Herlev, Denmark

Requests for reprints: Brian Law, Cancer/Genetics Research Complex, University of Florida, 1376 Mowry Road, Room 275G, P.O. Box 103633, Gainesville, FL 32610-3633. Phone: 352-273-8180; Fax: 352-273-8285; E-mail: bklaw{at}pharmacology.ufl.edu.

Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1–Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMTV) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV–cyclin D1–Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-D1K2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor ß (TGFß), but are relatively resistant to TGFß antiproliferative effects. Fibroblasts derived from MMTV-D1K2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70^s6k and Akt on activating sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGFß and HGF, resulting in desmoplasia. The MMTV-D1K2 mice should provide a useful model system for the development of therapeutic approaches to block the stromal desmoplastic reaction that likely plays an important role in the progression of multiple types of human tumors. [Cancer Res 2007;67(7):3135–44]

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