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The Biology Behind Microphthalmic-Associated Transcription Factor Integrates Melanocyte Biology and Melanoma Progression 55 Commentary on Koyanagi et al., p.1137 Colin Goding 1 and Frank L. Meyskens, Jr. 2 Introduction and Historical Background In this issue of Clinical Cancer Research, Koyanagi et al. (1) present results that indicate that microphthalmic-associated transcription factor (Mitf) levels as measured in circulating tumor cells correlate to stage of disease and thereby further support the notion that this transcription factor is proprolifer- ative. Of particular interest is that the rate of detection of Mitf in circulating tumor cells is considerably higher than that which has been reported for assessment of this marker in pathologic specimens. This suggests that factors, perhaps undescribed, are functioning to up-regulate Mitf in vivo that are not present or suppressed in vitro. The clinical outcome of primary melanoma has improved over the last 25 years in large part secondary to earlier diagnosis and appropriate surgical management. Once malignant cells have spread beyond the cutaneous compartment, treatment of the disease and outcome remain poor. An understanding of the role of molecular aberrations that exist in melanoma has been a long time in coming because many aberrations exist and separating the important from the secondary has been difficult. The identification in melanoma of clonal abnormalities in the sea of aneuroploidy that characterizes the advanced disease (2) and the recognition that these chromosomal abnormalities had prognostic implications were important early advances (3). The recent identification of distinct sets of genetic alterations by chromosomal genomic hybridization in primary melanomas in different geographic body sites with different UV exposures is an important contribution and identifies subsets of melanoma with distinct genetic pathways (ref. 4; commentary in ref. 5). Over the last 25 years, a number of investigators have identified the involvement of many growth factors and signaling pathways in melanoma (6, 7). In general, however, these alter- ations were only loosely linked to the unique features of mela- nocyte biology. Mitf, the molecule being discussed in this commentary, has its historical origins in the efforts of a German scientist who, over 60 years ago, discovered and described the Authors’ Affiliations: 1 Signalling and Development Laboratory, Marie Curie Research Institute, Surrey, United Kingdom and 2 Chao Family Comprehensive Cancer Center, University of California, Irvine, California Received 12/6/05; accepted 12/12/05. Grant support: Marie Curie Cancer Care and the Association for International Cancer Research (C. Goding); National Cancer Institute grants CA 72294, CA62203, and CA88078, and the Oxnard and Waltmar Foundations (F.L. Meyskens). Requests for reprints: Frank L. Meyskens, Jr., University of California Irvine Medical Center, Room 215, Building 56, 101 The City Drive, Orange, CA 92868. Phone: 714-456-6310; Fax: 714-456-2240; E-mail: flmeyske @ uci.edu. F 2006 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-2648 www.aacrjournals.org first mouse Mitf mutation, white mice with small eyes (8), and in the clinical observations of a Dutch ophthalmologist, Dr. Petrius Waardenburg, who first noticed that people with different colored eyes often had a hearing impairment and described the syndrome now classified as Waardenburg syndrome type 2 (9). In 1971, Arias (10) defined the phenotype of Waardenburg syndrome type 2 as individuals without dystopic canthorum and it is in this group in which autosomal dominant mutations of the Mitf gene are transmitted. Melanocytes originate in the neural crest and migrate as nonpigmented melanoblasts to their final destinations, includ- ing the epidermis and hair follicle, the choroid of the eye, and the inner ear. Differentiation of these cells leads to the manufacture of the pigment melanin that provides skin, hair, and eye color, and protection against solar UV irradiation. Importantly, malignant transformation of the melanocyte characterized by activating mutations in BRAF or NRAS coupled, for example, to loss of cell cycle control, although mutations in the INK4a/Arf locus, together with suppression of senescence, gives rise to malignant melanoma, a highly aggressive and increasingly common disease. Mtif, Survival, and Development Recently, the attention of many researchers interested in melanocyte biology and development and those occupied with understanding melanoma has converged on a remarkable gene that seems to coordinate almost every aspect of pigment cell behavior. The gene encoding the basic-helix-loop-helix- leucine zipper, Mitf, was first isolated as a consequence of transgenic insertions that rendered the gene inactive (11, 12). The resulting Mitf-null mice were completely white and exhibited a micropthalmic phenotype from a failure of the neural crest – derived melanocytes population to survive and the retinal pigment epithelium to differentiate during devel- opment. These mice were also deaf because the melanocyte population in the inner ear is required for function of the stria vascularis (13). Studies from many groups (reviewed in ref. 14) went on to show that Mitf was not only critical to melanoblasts survival, but also played a key role in coordinating the expression of genes, such as tyrosinase and Tyrp-1, required for the manufac- ture of pigment and the genesis of a functional melanosome by binding to a specific subset of E-box motifs in their promoters. These elements, frequently termed M-boxes, char- acterized by a core CATGTG element flanked by either a 5V T and/or 3VA residue (15), enable Mitf to activate transcription of target genes through recruitment of the cyclic AMP (cAMP)- responsive element binding protein (CREB) – binding protein/ p300 transcription cofactors (16). Clin Cancer Res 2006;12(4) February 15, 2006 Downloaded from clincancerres.aacrjournals.org on December 18, 2014. © 2006 American Association for Cancer Research.

Microphthalmic-associated transcription factor integrates melanocyte biology and melanoma progression.