LRIG Proteins in mammary gland development and carcinogenesis

描述（由申请人提供）：该项目的重点是跨膜富含亮氨酸重复蛋白Lrig 1的机制分析。Lrig蛋白最近作为与乳腺生物学和肿瘤发生相关的膜受体的新型调节剂出现，包括ErbB途径的成员。该建议的中心假设是Lrig 1在致癌受体的转录后调节中起关键作用，并且乳腺癌中Lrig 1的扰动有助于异常受体表达，影响肿瘤的发生和/或进展。在这个建议中，我们将集中精力在两个独立的目标，这将扩大我们的知识的LRig 1在乳腺生物学和肿瘤发生的功能。在目标1中，我们将利用Lrig 1基因敲除小鼠来确定Lrig 1在乳腺发育和癌基因驱动的肿瘤发展中的作用。在目标2中，我们将研究Lrig 1在雌激素受体-a和ErbB 2之间的串扰中的作用，以及对内分泌抵抗的影响。 公共卫生相关性：这项研究将研究跨膜富含亮氨酸重复蛋白Lrig 1在乳腺发育和癌变中的作用。Lrig 1最近已成为包括ErbB 2在内的致癌受体的关键转录后调节因子。关于受体表达的转录后调控知之甚少。填补这些知识“空白”可能会暴露出可用于改善乳腺癌治疗的机会。

DESCRIPTION (provided by applicant): This project focuses on a mechanistic analysis of the transmembrane leucine-rich repeat protein Lrig1. Lrig proteins have recently emerged as novel modulators of membrane receptors with relevancy to mammary gland biology and tumorigenesis, including members of the ErbB pathway. The central hypothesis of this proposal is that Lrig1 plays a critical role in the post-transcriptional regulation of oncogenic receptors ad that perturbation of Lrig1 in breast cancer contributes to aberrant receptor expression, impacting tumor initiation and /or progression. In this proposal, we will focus our efforts on two independent aims which will expand our knowledge of the function of the Lrig1 in mammary gland biology and tumorigenesis. In Aim 1, we will exploit the Lrig1 knockout mice to define the role of Lrig1 in mammary gland development and oncogene-driven tumor development. In Aim 2, we will examine the role of Lrig1 in crosstalk between the estrogen receptor-a and ErbB2 with implications for endocrine resistance. PUBLIC HEALTH RELEVANCE: The proposed research will examine the role of the transmembrane leucine-rich repeat protein Lrig1 in mammary gland development and carcinogenesis. Lrig1 has recently emerged as a key post-transcriptional regulator of oncogenic receptors including ErbB2. Relatively little is known about the post-transcriptional regulation of receptor expression. Filling these knowledge "gaps" may expose opportunities which can be exploited to improve breast cancer treatment.