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Automated Quantitative Analysis of Activator Protein-2 Subcellular Expression in Melanoma Tissue Microarrays Correlates with Survival Prediction

Departments of ¹ Cancer Biology, ² Pathology, ³ Surgical Oncology, and ⁴ Biostatistics and Applied Mathematics, University of Texas M.D. Anderson Cancer Center; ⁵ ApoCell, Houston, Texas; and ⁶ Department of Pathology, Yale University, New Haven, Connecticut

Requests for reprints: Darren W. Davis, ApoCell, Inc., 8030 El Rio, Houston, TX 77054. Phone: 713-440-6070; Fax: 713-440-6074; E-mail: ddavis{at}apocell.com.

The activator protein-2 (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.

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