Deciphering the Tissue Specificity of MEN1 Related Tumorigenesis

描述（由申请人提供）：我们的研究申请解决PQ8：“为什么某些突变事件在某些组织中促进癌症表型而在其他组织中不促进？”我们提出的研究目标是确定肿瘤抑制基因失活后导致组织选择性肿瘤发生的因素。多发性内分泌肿瘤1型（MEN1）是一种以组织限制性肿瘤发生为特征的家族性癌症综合征，为实现这一目标提供了一种独特且易于处理的模型。Men1是一种编码menin转录因子的普遍表达的肿瘤抑制因子，它的双等位基因失活是Men1肿瘤发生所必需的。我们使用Cre-lox缺失Men1的实验表明，Men1在不同组织中的差异失活并不能解释Men1肿瘤的组织限制性。相反，需要其他因素来增强或抑制失去Men1的组织中的肿瘤发生。例如，胰腺所有细胞中Men1的纯合缺失会导致内分泌组织而非外分泌组织的肿瘤

DESCRIPTION (provided by applicant): Our research application is addressing PQ8: "Why do certain mutational events promote cancer phenotypes in some tissues and not in others?" The goal of our proposed research is to identify factors responsible for tissue-selective tumorigenesis following inactivation of a tumor suppressor gene. Multiple Endocrine Neoplasia type 1 (MEN1), a familial cancer syndrome characterized by tissue-restricted tumorigenesis, provides a unique and tractable model with which to accomplish this goal. Bi-allelic inactivation of Men1, a ubiquitously expressed tumor suppressor encoding the transcription factor menin, is required for tumorigenesis in MEN1. Our experiments using Cre-lox deletion of Men1 demonstrates that differential inactivation of Men1 in various tissues does not explain the tissue restricted nature of tumors in MEN1. Rather, additional factors are required to enhance or suppress tumorigenesis in tissues that have lost Men1. For example, homozygous deletion of Men1 in all cells of the pancreas results in tumors in the endocrine tissue but not exocrine tissue of the same organ. Given that inactivation of Men1 is tightly linked to MEN1, we postulate that operation of these modulating factors is regulated by loss of menin. Our central hypothesis is that loss of menin differentially regulates expression of factors that influence carcinogenesis in various tissues so as to generate the tissue restricted characteristic of tumor formation in MEN1. To test this hypothesis, we propose to undertake both unbiased, genome wide screens and candidate approaches to identify relevant factors. Aim 1 employs ChIP- Seq and RNA-Seq respectively to identify DNA binding sites for menin that are differentially occupied and transcriptomes that are differentially expressed in tissues that develop MEN1 tumors versus those that do not. Specifically, we will compare tissues from the endocrine pancreas (develops tumors) versus the exocrine pancreas (does not develop tumors). Aim 2 will validate these findings in the parathyroid gland, a second site of tumor development in MEN1. Aim 3 will explore the role of the candidate protein ARC, an apoptosis inhibitor and cell cycle promoter that has already been implicated in mammary carcinogenesis. Our preliminary studies show that ARC is up-regulated by deletion of Men1 in the endocrine pancreas and parathyroid gland, but not in the exocrine pancreas. Moreover, ChIP-CHIP studies suggest that menin binds to the promoter of nol3, the gene encoding ARC. Taken together, these studies will provide novel and important insights into why tumors develop in some tissues and not in others following loss of a tumor suppressor gene.