Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression.
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 beta (TGFbeta), but are relatively resistant to TGFbeta 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 TGFbeta 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.
Corsino
Patrick
P
Department of Pharmacology and Therapeutics and the Shands Cancer Center, University of Florida, Gainesville, Florida, USA.
Davis
Bradley
B
Law
Mary
M
Chytil
Anna
A
Forrester
Elizabeth
E
Nørgaard
Peter
P
Teoh
Nicole
N
Law
Brian
B
D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D006965:Hyperplasia; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000473:pathology / Q000821:virology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
C493838:Rbl2 protein, mouse; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D017228:Hepatocyte Growth Factor; D051357:Cyclin-Dependent Kinase 2