Spontaneous and UVR-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice

Hacker, Elke, Muller, H. Konrad, Irwin, Nicole, Gabrielli, Brian, Lincoln, Doug, Pavey, Sandra, Broome-Powell, Marianne, Malumbres, Marcos, Barbacid, Mariano, Hayward, Nicholas K., & Walker, Graeme J. (2006) Spontaneous and UVR-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice. Cancer Research, 66(6), pp. 2946-2952.

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Human melanoma susceptibility is often characterized by germline 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 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 greatly increase susceptibility to melanoma in mice. While UVR treatment failed to induce melanomas in Cdk4R24C/R24C mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4R24C/R24C/TPras animals, compared to TPras alone. This increased penetrance was dependant on the threshold of Cdk4 activation, as Cdk4R24C/+/TPras animals did not show an increase in UVR-induced melanoma penetrance compared to TPras alone. In addition, Cdk4R24C/R24C/TPras mice invariably developed multiple primary lesions, which occurred rarely in TPras mice. These results indicate that germline defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4R24C/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 Cdk4R24C/R24C/TPras mice, but not TPras mice, readily metastasized to regional lymph nodes. Thus it appears that in the mouse, Hras activation initiates UVR-induced melanoma development, while the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing larger, more aggressive, metastatic tumors.

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36 citations in Web of Science®
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ID Code: 21112
Item Type: Journal Article
Refereed: Yes
Additional Information: Running title: UVR-induced melanomas in Cdk4R24C/R24C/TPras mice
Additional URLs:
Keywords: Transgenic mouse, Metastatic melanoma, Ultraviolet radiation, Ras, Cdk4
DOI: 10.1158/0008-5472.CAN-05-3196
ISSN: 0008-5472
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PUBLIC HEALTH AND HEALTH SERVICES (111700) > Public Health and Health Services not elsewhere classified (111799)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright 2006 American Association for Cancer Research
Deposited On: 11 Jun 2009 22:28
Last Modified: 24 Jun 2017 14:40

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