Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4(R24C/R24C)/TPras mice

Hacker, E., Muller, H. K., Irwin, N., Gabrielli, B., Lincoin, D., Pavey, S., Powell, M. B., Malumbres, M., Barbacid, M., Hayward, N. and Walker, G. (2006) Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4(R24C/R24C)/TPras mice. Cancer Research, 66 6: 2946-2952. doi:10.1158/0008-5472.CAN-05-3196

Author Hacker, E.
Muller, H. K.
Irwin, N.
Gabrielli, B.
Lincoin, D.
Pavey, S.
Powell, M. B.
Malumbres, M.
Barbacid, M.
Hayward, N.
Walker, G.
Title Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4(R24C/R24C)/TPras mice
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2006
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-05-3196
Volume 66
Issue 6
Start page 2946
End page 2952
Total pages 7
Editor F. J. Rauscher
G. C. Prendergast
M. F. Roussel
Place of publication United States
Publisher American Association for Cancer Research
Collection year 2006
Language eng
Subject C1
321015 Oncology and Carcinogenesis
730108 Cancer and related disorders
110304 Dermatology
111201 Cancer Cell Biology
111203 Cancer Genetics
111207 Molecular Targets
Abstract Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4(R24C/R24C) mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4(R24C/R24C)/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4(R24C/+)/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4(R24C/R24C)/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4(R24C/R24C)/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4(R24C/R24C)/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors.
Keyword Oncology
Tpras Transgenic Mice
Braf Mutations
Tumor Suppression
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 10:01:09 EST