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Molecular and Cellular Biology, May 2005, p. 4176-4188, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.4176-4188.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of Epidermal Growth Factor Receptor Signaling in RAS-Driven Melanoma{dagger}

Nabeel Bardeesy,1,{ddagger}* Minjung Kim,1,{ddagger} Jin Xu,1 Ryung-Suk Kim,2 Qiong Shen,1 Marcus W. Bosenberg,3 Wing H. Wong,2 and Lynda Chin1,4*

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts,1 Departments of Statistics and Biostatistics, Harvard University, Cambridge, Massachusetts,2 Department of Pathology, University of Vermont, Burlington, Vermont,3 Department of Dermatology, Harvard Medical School, Boston, Massachusetts4

Received 17 August 2004/ Returned for modification 15 September 2004/ Accepted 25 January 2005

The identification of essential genetic elements in pathways governing the maintenance of fully established tumors is critical to the development of effective antioncologic agents. Previous studies revealed an essential role for H-RASV12G in melanoma maintenance in an inducible transgenic model. Here, we sought to define the molecular basis for RAS-dependent tumor maintenance through determination of the H-RASV12G-directed transcriptional program and subsequent functional validation of potential signaling surrogates. The extinction of H-RASV12G expression in established tumors was associated with alterations in the expression of proliferative, antiapoptotic, and angiogenic genes, a profile consistent with the observed phenotype of tumor cell proliferative arrest and death and endothelial cell apoptosis during tumor regression. In particular, these melanomas displayed a prominent RAS-dependent regulation of the epidermal growth factor (EGF) family, leading to establishment of an EGF receptor signaling loop. Genetic complementation and interference studies demonstrated that this signaling loop is essential to H-RASV12G-directed tumorigenesis. Thus, this inducible tumor model system permits the identification and validation of alternative points of therapeutic intervention without neutralization of the primary genetic lesion.

* Corresponding author. Present address for Nabeel Bardeesy: Massachusetts General Hospital Cancer Center, 13th St., Bldg. 148, Room 7204, Charlestown, MA 02129. E-mail: nelbardeesy{at}partners.org. Mailing address for Lynda Chin: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-6091. Fax: (617) 632-6069. E-mail: Lynda_chin{at}dfci.harvard.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally.

Molecular and Cellular Biology, May 2005, p. 4176-4188, Vol. 25, No. 10
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.10.4176-4188.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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