Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor β resistance and acquire paracrine mitogenic stimulation during progression

被引:20
作者
Corsino, Patrick
Davis, Bradley
Law, Mary
Chytil, Anna
Forrester, Elizabeth
Norgaard, Peter
Teoh, Nicole
Law, Brian
机构
[1] Univ Florida, Dept Pharmacol & Therapeut, Gainesville, FL 32610 USA
[2] Univ Florida, Shands Canc Ctr, Gainesville, FL 32610 USA
[3] Vanderbilt Univ, Dept Canc Biol, Nashville, TN USA
[4] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA
[5] Copenhagen Univ Hosp, Dept Pathol, Herlev, Denmark
关键词
D O I
10.1158/0008-5472.CAN-06-3815
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (MMITV) 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-DIK2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor beta (TGF beta), but are relatively resistant to TGF beta antiproliferative effects. Fibroblasts derived from MMTV-DIK2 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 TGF beta and HGF, resulting in desmoplasia. The MMTV-DIK2 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.
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收藏
页码:3135 / 3144
页数:10
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