title: β-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas.
abstract: Malignant melanoma is characterized by frequent metastasis, however, specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating β-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and Braf(V600E) mutation, we demonstrate that β-catenin is a central mediator of melanoma metastasis to the lymph nodes and lungs. In addition to altering metastasis, β-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with β-catenin stabilization are very similar to a subset of human melanomas. Together these findings establish Wnt signaling as a metastasis regulator in melanoma.
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA. william.damsky@uvm.edu
authors.forename: William E
authors.initials: WE
authors.lastname: Damsky
authors.forename: David P
authors.initials: DP
authors.lastname: Curley
authors.forename: Manjula
authors.initials: M
authors.lastname: Santhanakrishnan
authors.forename: Lara E
authors.initials: LE
authors.lastname: Rosenbaum
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.forename: Bonnie E
authors.initials: BE
authors.lastname: Gould Rothberg
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: David
authors.initials: D
authors.lastname: Dankort
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001549:Benzamides; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000556:secondary; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008207:Lymphatic Metastasis; D008544:Melanocytes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D055550:Protein Stability; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D013160:Splenic Neoplasms / Q000556:secondary; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D051176:beta Catenin; D000068877:Imatinib Mesylate; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse