The Role of Beta-catenin Signaling in Malignant Melanoma

描述(申请人提供)：黑色素瘤是一种常见的疾病，通常是致命的。2004年，美国将出现大约5万例新病例和8000例与黑色素瘤相关的死亡病例。早期转移是黑色素瘤的特征，是一个不祥的征兆，因为目前的治疗干预措施对存活率影响甚微。缺乏准确的预后指标和有效的治疗方法强调了更好地了解黑色素瘤形成和发展中的遗传和表型变化的必要性。约70%的黑色素瘤和黑色素细胞痣中存在BRAF的激活突变，并与黑色素瘤的MAP激酶信号转导有关。家族性和散发性黑色素瘤的一个子集涉及编码重叠的肿瘤抑制基因p16INK4A和p14ARF的CDKN2A基因突变。观察到β-连环蛋白的激活突变以低但可重复性的速度发生，这增加了结构性WNT途径信号可能导致黑色素瘤的可能性。在没有激活β-连环蛋白突变的情况下，大约40%的黑色素瘤中WNT途径激活的特征支持了这一假说。我们的目标是评估β-连环蛋白在良性黑素细胞中的激活以及在小鼠黑色素瘤形成中的作用。这些研究将依赖于使用Cre-lox重组来有条件地激活β-连环蛋白，并将利用一种新的小鼠品系，该品系在我们已经产生和表征的黑素细胞中特异地表达他莫昔芬诱导形式的Cre。我们将利用这个小鼠模型从功能上评估黑素细胞特异性激活剂β-连环蛋白对以下方面的影响：1)。黑素细胞在体外和体内的增殖、分化和迁移。黑色素瘤的形成伴随着CDnk2a丢失、Pten丢失或HRAs激活。此外，我们还将确定：黑素细胞干细胞和黑色素瘤形成之间的关系，干细胞区外黑素细胞的复制潜力，并将使用400个样本组织微阵列检查人类黑色素瘤中的β-连环蛋白信号靶标。

DESCRIPTION (provided by applicant): Melanoma is a common disease that is frequently lethal. About 50,000 new cases and 8,000 melanoma-related deaths will occur in the US in 2004. Early metastases are characteristic of melanoma and are an ominous sign, as current therapeutic interventions have little effect on survival. The lack of accurate prognostic indicators and effective therapies emphasize the need for a better understanding of the genetic and phenotypic changes in melanoma formation and progression. Activating mutations in BRAF occur in about 70% of melanomas and melanocytic nevi and implicate MAP kinase pathway signaling in melanoma. A subset of familial and sporadic melanomas have mutations involving the CDKN2A locus encoding the overlapping tumor suppressor genes p16INK4A and p14ARF. The observation that activating mutations in beta-catenin occur at a low but reproducible rate raises the possibility that constitutive WNT pathway signaling may result in melanoma. This hypothesis is supported by features of WNT pathway activation in roughly 40% of melanomas in the absence of activating beta-catenin mutations. Our goal is to evaluate the role of beta-catenin activation in benign melanocytes and on melanoma formation in mice. These studies will rely on conditional activation of beta-catenin using Cre-lox recombination and will utilize a new mouse strain expressing a tamoxifen-inducible form of Cre specifically in melanocytes that we have generated and characterized. We will utilize this mouse model to functionally evaluate the effects of melanocyte-specific activatior of beta-catenin on: 1). melanocyte proliferation, differentiation, and migration in vitro and in vivo 2). melanoma formation in conjunction with Cdnk2a loss, Pten loss or Hras activation and 3). melanoma progression to metastasis Additionally, we will determine: the relationship between melanocyte stem cells and melanoma forfnation, the replicative potential of melanocytes outside of the stem cell niche, and will examine beta-catenin signaling targets in human melanoma using a 400 sample tissue microarray.