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The origin of tumor heterogeneity is poorly understood, yet it represents a major barrier to effective therapy. In melanoma and in melanocyte development, the microphthalmia-associated transcription factor (Mitf) controls survival, differentiation, proliferation, and migration/metastasis. The Brn-2 (N-Oct-3, POU3F2) transcription factor also regulates melanoma proliferation and is up-regulated by BRAF and beta-catenin, two key melanoma-associated signaling molecules. Here, we show that Brn-2 also regulates invasiveness and directly represses Mitf expression. Remarkably, in melanoma biopsies, Mitf and Brn-2 each mark a distinct subpopulation of melanoma cells, providing a striking illustration of melanoma tumor heterogeneity with implications for melanoma therapy.

Original publication




Journal article


Cancer Res

Publication Date





7788 - 7794


Animals, Base Sequence, Biomarkers, Tumor, Down-Regulation, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Melanoma, Mice, Mice, Inbred BALB C, Mice, Nude, Microphthalmia-Associated Transcription Factor, Molecular Sequence Data, Neoplasm Invasiveness, POU Domain Factors, Protein Binding, Transplantation, Heterologous, Tumor Cells, Cultured