| First Author | Dankort D | Year | 2009 |
| Journal | Nat Genet | Volume | 41 |
| Issue | 5 | Pages | 544-52 |
| PubMed ID | 19282848 | Mgi Jnum | J:151023 |
| Mgi Id | MGI:4352618 | Doi | 10.1038/ng.356 |
| Citation | Dankort D, et al. (2009) Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41(5):544-52 |
| abstractText | Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease. |
