Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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Down-Regulation
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Female
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Gene Expression Regulation, Neoplastic
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Homeodomain Proteins / physiology*
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Humans
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Melanoma / genetics*
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Microphthalmia-Associated Transcription Factor / genetics*
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Microphthalmia-Associated Transcription Factor / metabolism
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Molecular Sequence Data
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Neoplasm Invasiveness
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POU Domain Factors / genetics
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POU Domain Factors / metabolism
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POU Domain Factors / physiology*
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Protein Binding
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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Biomarkers, Tumor
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Homeodomain Proteins
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Microphthalmia-Associated Transcription Factor
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POU Domain Factors
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transcription factor Brn-2