title: AKT1 Activation Promotes Development of Melanoma Metastases.
abstract: Metastases are the major cause of melanoma-related mortality. Previous studies implicating aberrant AKT signaling in human melanoma metastases led us to evaluate the effect of activated AKT1 expression in non-metastatic BRAF(V600E)/Cdkn2a(Null) mouse melanomas in vivo. Expression of activated AKT1 resulted in highly metastatic melanomas with lung and brain metastases in 67% and 17% of our mice, respectively. Silencing of PTEN in BRAF(V600E)/Cdkn2a(Null) melanomas cooperated with activated AKT1, resulting in decreased tumor latency and the development of lung and brain metastases in nearly 80% of tumor-bearing mice. These data demonstrate that AKT1 activation is sufficient to elicit lung and brain metastases in this context and reveal that activation of AKT1 is distinct from PTEN silencing in metastatic melanoma progression. These findings advance our knowledge of the mechanisms driving melanoma metastasis and may provide valuable insights for clinical management of this disease.
authors.affiliation: Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Robinson
authors.affiliation: Department of Chemistry, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: Rowan A
authors.initials: RA
authors.lastname: Arave
authors.affiliation: Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Burnett
authors.affiliation: Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Kircher
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: Allie H
authors.initials: AH
authors.lastname: Grossmann
authors.affiliation: Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: VanBrocklin
authors.affiliation: Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA. Electronic address: sheri.holmen@hci.utah.edu.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Holmen
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002642:Chick Embryo; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C514862:Akt1 protein, mouse; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse