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Brn-2 Represses Microphthalmia-Associated Transcription Factor Expression and Marks a Distinct Subpopulation of Microphthalmia-Associated Transcription Factor–Negative Melanoma Cells

¹ Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey, United Kingdom; ² Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford, United Kingdom; ³ Developmental Genetics of Melanocytes, UMR146 Centre National de la Recherche Scientifique, Institut Curie, Centre Universitaire, Orsay Cedex France; ⁴ IGBMC, Illkirch Cedex, France; ⁵ FIRC Institute of Molecular Oncology, Milano, Italy; and ⁶ Melanogenix Group, Institute for Molecular Bioscience, Queensland Bioscience Precinct, The University of Queensland, Brisbane, Queensland, Australia

Requests for reprints: Colin R. Goding, Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey, RH8 OTL, United Kingdom. Phone: 44-1883-722306; Fax: 44-1883-714375; E-mail: c.goding{at}mcri.ac.uk.

Key Words: Brn-2 • melanoma • Mitf

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 β-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. [Cancer Res 2008;68(19):7788–94]

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