Analysis of Modifiers of Mammary Tumor Susceptibility

描述(申请人提供)：癌症是一种多基因疾病，涉及多种基因产物和多种细胞类型的相互作用。虽然人们把大量精力放在识别对肿瘤发展过程有重大影响的单基因上，但很明显，任何一种单一的基因变化都不足以让正常细胞变得恶性。虽然肿瘤细胞中存在多种基因变化，但肿瘤发展的一个方面是在癌症发展过程中未发生突变的基因功能的自然变异所起的作用。确定这些“修饰基因”或“易感基因”的功能对于理解肿瘤的发展过程至关重要。小鼠是进行这类研究的极佳模型。携带ApcMin等位基因的小鼠更容易患上乳腺增生症和肿瘤。遗传背景影响这些小鼠乳腺的病变类型、病变数量和肿瘤潜伏期。B6ApcMin/小鼠在暴露于致癌物后迅速发展为乳腺鳞状细胞癌。FVBxB6 ApcMin/小鼠在相同的治疗后，主要发生肺泡增生和罕见的癌症。为了确定导致这种表型差异的基因，进行了回交分析，并确定了几个修饰基因座。该项目的目标是：1)产生同源FVB ApcMin/小鼠，以便更完整地描述遗传背景的影响；2)产生并鉴定携带其中一种修饰基因Mmo2的FVB或129等位基因的小鼠的同源系；3)将Mmo2定位到足够小的区间，以便能够对这些基因座进行遗传识别；4)进一步表征Mmo2所赋予的分子表型；以及5)利用基因表达的变化来确定受Mmo2影响的分子途径。这些研究的最终目标是确定编码Mmo2的基因，并了解其对肿瘤发展的影响。了解这种基因产物如何改变启动细胞的命运，将有助于为被诊断为乳腺癌前病变的女性开发有针对性的治疗和治疗策略。公共卫生相关性：乳腺癌表现出强烈的家族性倾向，但大多数病例不能归因于主基因的影响。因此，大多数乳腺癌病例将是由于影响较小但影响显著的基因的总和。这个项目的目标是使用老鼠模型来识别和表征一个这样的基因座的功能。

DESCRIPTION (provided by applicant): Cancer is a multigenic disease that involves the interplay of many gene products and many cell types. While much concentration has been placed on the identification of single genes that have a large effect on the process of tumor development, it is clear that no one single genetic change is sufficient for a normal cell to become malignant. While multiple genetic changes are present in tumor cells, one aspect of tumor development is the role of natural variation in the function of genes that are not mutated in cancer development. Determining the function of these "modifier" or "susceptibility" genes is vital to understanding the process of tumor development. Mice are excellent models with which to perform this type of study. Mice carrying the ApcMin allele are predisposed to develop mammary hyperplasias and tumors. Genetic background affects the type of lesion, the number of lesions, and tumor latency in the mammary glands of these mice. B6 ApcMin/+ mice rapidly develop squamous cell carcinomas of the mammary gland after exposure to a carcinogen. FVBxB6 ApcMin/+ mice develop mainly alveolar hyperplasias and carcinomas only rarely after the same treatment. To identify the genes responsible for this phenotypic difference, a backcross analysis was performed and several modifier loci have been identified. The goals of this project are to 1) generate congenic FVB ApcMin/+ mice in order to characterize the effect of the genetic background more completely; 2) generate and characterize congenic lines of mice that carry either the FVB or 129 allele of one of the modifiers, Mmom2; and 3) to map Mmom2 to a interval small enough to allow genetic identification of the loci;4) to further characterize the molecular phenotype conferred by Mmom2; and 5) to use changes in gene expression to identify molecular pathways affected by Mmom2. The ultimate goals of these studies are to identify the gene encoding Mmom2 and understand the effect on tumor development. Understanding how this gene product can alter the fate of initiated cells will inform the development of targeted treatments and treatment strategies for women who have been diagnosed with preneoplastic lesions in the breast. PUBLIC HEALTH RELEVANCE: Breast cancer shows a strong familial tendency, but most cases cannot be ascribed to the effect of major genes. Thus, most cases of breast cancer will be due to the sum of the effects of genes with smaller, though significant effects. The goal of this project is to identify and characterize the function of one such locus using a mouse model.