IRS-2 Function in Tumor Progression and Metastasis

描述(申请人提供)：本提案的总体目标是研究胰岛素受体底物-2(IRS-2)调节肿瘤细胞代谢以促进乳腺癌进展和转移的机制。IRS蛋白是适配器分子，被招募到激活的细胞表面受体，在那里它们组织信号复合体来启动下游的信号级联。许多通过IRS蛋白发出信号的受体与乳腺癌有关，这突显了了解这些细胞质分子如何影响肿瘤细胞功能的重要性。在人类中，IRS-1和IRS-2在正常和良性乳腺组织、DCIS和浸润性乳腺癌中都有表达。然而，这些接头蛋白在乳腺肿瘤进展中扮演着不同的角色。具体地说，在缺乏IRS-2的情况下，转移能力显著减弱，但在缺乏IRS-1但增加了IRS-2的表达和激活的肿瘤细胞中，转移能力得到增强。在体外，通过IRS-2信号通路促进肿瘤细胞的迁移、侵袭和存活。尽管IRS1和IRS2之间的功能差异已经被发现，但这些高度同源的蛋白调节不同细胞结果以响应共同刺激的机制(S)仍然未知。为了预测IRS-1和IRS-2的相对表达对乳腺癌患者的影响，并确定如何操纵它们的表达和功能来干扰乳腺癌的进展，需要对这些适配蛋白进行更多的机制研究。申请人实验室最近的研究表明，IRS-2，而不是IRS-1，在调节糖酵解以促进肿瘤细胞存活和侵袭方面发挥着重要作用。此外，低氧会增加IRS-2的表达，从而影响肿瘤的代谢状态，促进侵袭性行为。这项建议中要检验的总体假设是，IRS-2是一种必要的低氧反应基因，通过调节肿瘤细胞的代谢促进乳腺癌的进展和转移。为了研究这一假设，申请人建议：1)确定IRS-2调节乳腺癌细胞新陈代谢的机制。IRS-2通过靶向激活PI3K/mTOR信号来调节GLUT1的表面表达，从而促进葡萄糖摄取和有氧糖酵解的假说将被检验；2)研究缺氧促进IRS-2表达的机制，并确定这种调节在乳腺癌代谢和进展中的功能意义。在低氧环境中，IRS-2的表达在基因转录水平上增加，以维持乳腺癌细胞的代谢，促进肿瘤的进展和转移，这一假设将得到验证。 公共卫生相关性：转移是癌症患者死亡的主要原因，需要新的方法来阻止或治疗转移肿瘤。新陈代谢自给自足的肿瘤细胞可以在缺乏氧气和其他产生能量所必需的营养物质的压力环境中生存，这就产生了一种选择性压力，使其发展为侵袭性和转移性疾病。在这项提案中，将研究肿瘤细胞调节代谢以促进转移的一种机制，长期目标是开发新的治疗方法，使有转移肿瘤的癌症患者受益。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to investigate the mechanism by which Insulin Receptor Substrate-2 (IRS- 2) regulates tumor cell metabolism to promote breast cancer progression and metastasis. The IRS proteins are adaptor molecules that are recruited to activated cell surface receptors where they organize signaling complexes to initiate downstream signaling cascades. Many of the receptors that signal through the IRS proteins have been implicated in breast cancer, which highlights the importance of understanding how these cytoplasmic molecules impact tumor cell function. In humans, both IRS-1 and IRS-2 are expressed in normal and benign breast tissue, DCIS and invasive breast cancer. However, these adaptor proteins play divergent roles in mammary tumor progression. Specifically, metastasis is significantly impaired in the absence of IRS-2, but it is enhanced in tumor cells that lack IRS-1, but have increased IRS-2 expression and activation. In vitro, signaling through IRS-2 promotes tumor cell migration, invasion and survival. Although functional differences between IRS-1 and IRS-2 have been identified, the mechanism(s) by which these highly homologous proteins regulate distinct cellular outcomes in response to common stimuli remains unknown. To predict the consequences of the relative expression of IRS-1 and IRS-2 for breast cancer patients and to determine how their expression and function could be manipulated to interfere with breast cancer progression, additional mechanistic studies of these adaptor proteins are needed. Recent studies in the applicant's lab reveal that IRS-2, but not IRS-1, plays an essential role in regulating glycolysis to promote tumor cell viability and invasion. Furthermore, IRS-2 expression is increased by hypoxia, which impinges upon the metabolic status of tumors to promote aggressive behavior. The overall hypothesis to be examined in this proposal is that IRS-2 is an essential hypoxia-responsive gene that promotes breast cancer progression and metastasis through the regulation of tumor cell metabolism. To investigate this hypothesis, the applicant proposes to: 1) Determine the mechanism by which IRS-2 regulates metabolism in breast carcinoma cells. The hypothesis that IRS-2 enhances glucose uptake and promotes aerobic glycolysis through the targeted activation of PI3K/mTOR signaling to regulate the surface expression of GLUT1 will be examined; and 2) Investigate the mechanism by which hypoxia enhances IRS-2 expression and define the functional significance of this regulation for breast cancer metabolism and progression. The hypothesis that IRS-2 expression is increased in hypoxic environments at the level of gene transcription to sustain breast carcinoma cell metabolism and to promote tumor progression and metastasis will be examined. PUBLIC HEALTH RELEVANCE: Metastasis is the leading cause of death for cancer patients and novel approaches to impede or treat metastatic tumors are needed. Tumor cells that develop metabolic self-sufficiency can survive in stressful environments that lack oxygen and other essential nutrients for energy production, and this creates a selective pressure to progress to invasive and metastatic disease. In this proposal, one mechanism by which tumor cells regulate their metabolism to promote metastasis will be examined with the long term goal of developing new therapies to benefit cancer patients with metastatic tumors.