title: Automated quantitative analysis of activator protein-2alpha subcellular expression in melanoma tissue microarrays correlates with survival prediction.
abstract: The activator protein-2alpha (AP-2) transcription factor plays a key role in regulating expression of genes involved in tumor growth and metastasis of human melanoma. We sought to assess the prognostic significance of AP-2 expression and its role in the transition of nevi to metastatic melanoma. Two cohorts were analyzed. One was a "progression" microarray containing melanoma specimens from M.D. Anderson Cancer Center representing 84 cases and the other was a retrospective cohort from Yale University representing 214 primary melanomas and 293 metastases. Analysis of total AP-2 expression using two quantitative systems [automated quantitative analysis (AQUA) and laser scanning cytometry (LSC)] revealed no correlation with diagnosis group. LSC analysis of the M.D. Anderson Cancer Center array showed that the number of cells expressing nuclear AP-2 was highest in the benign nevi group (11.85%) and significantly decreased in each phase of melanoma progression to 0.39% in the metastatic group. Both LSC and AQUA showed decreased nuclear AP-2 levels and increased cytoplasmic AP-2 that is directly proportional to progression. Neither nuclear nor cytoplasmic expression levels correlated with outcome. Intriguingly, the ratio of cytoplasmic to nuclear AP-2 predicted outcome in the entire population and in the primary tumors alone, demonstrating the power of the ratio to normalize for variations. Furthermore, the AP-2 ratio directly correlated with other clinicopathologic factors, including Breslow depth (R = 0.334, P < 0.001). We show that a high level of AP-2 expression in the cytoplasm relative to the nucleus correlates with poor prognosis and the loss of nuclear AP-2 expression is associated with malignant transformation and progression of melanoma.
authors.affiliation: Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Berger
authors.forename: Darren W
authors.initials: DW
authors.lastname: Davis
authors.forename: Carmen
authors.initials: C
authors.lastname: Tellez
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.forename: Marcella M
authors.initials: MM
authors.lastname: Johnson
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008545:Melanoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D040081:Protein Array Analysis / Q000379:methods; D050656:Transcription Factor AP-2 / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D050656:Transcription Factor AP-2