The Role of Beta-catenin Signaling in Malignant Melanoma

描述（由申请人提供）：黑色素瘤是一种常见的致命疾病。2004年，美国将出现大约5万例新病例和8000例与黑色素瘤有关的死亡。早期转移是黑色素瘤的特征，是一个不祥的迹象，因为目前的治疗干预对生存几乎没有影响。由于缺乏准确的预后指标和有效的治疗方法，因此需要更好地了解黑色素瘤形成和进展中的遗传和表型变化。BRAF的激活突变发生在约70%的黑色素瘤和黑素细胞痣中，并涉及黑色素瘤中的MAP激酶信号通路。家族性和散发性黑色素瘤的一个子集具有涉及编码重叠肿瘤抑制基因p16INK4A和p14ARF的CDKN2A位点的突变。观察到β -连环蛋白的激活突变以低但可重复的速率发生，这提高了构成性WNT通路信号传导可能导致黑色素瘤的可能性。这一假设得到了大约40%的黑色素瘤中WNT通路激活的特征的支持，这些特征在没有激活β -连环蛋白突变的情况下发生。我们的目标是评估β -连环蛋白在小鼠良性黑色素细胞和黑色素瘤形成中的作用。这些研究将依赖于使用Cre-lox重组的条件激活β -连环蛋白，并将利用一种新的小鼠品系，在我们已经产生和表征的黑素细胞中特异性表达他莫昔芬诱导形式的Cre。我们将利用该小鼠模型从功能上评估β -连环蛋白在以下方面的作用：1)体外和体内黑素细胞增殖、分化和迁移；2)与Cdnk2a缺失、Pten缺失或Hras激活相关的黑色素瘤形成；3)黑色素瘤进展到转移。黑素细胞干细胞与黑色素瘤形成之间的关系，干细胞生态位外黑素细胞的复制潜力，并将使用400个样本组织微阵列检测人类黑色素瘤中的β -连环蛋白信号靶点。

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.