Role of growth hormone in breast cancer

生长激素在乳腺癌中的作用

• 批准号: 7091580
• 负责人: STEVEN M SWANSON
• 金额: $ 32.35万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091580
• 关键词: apoptosis; biological signal transduction; breast neoplasms; carcinogenesis; genetically modified animals; growth factor receptors; hormone receptor; hormone regulation /control mechanism; immunocytochemistry; insulinlike growth factor; laboratory mouse; laboratory rat; mammary gland; neoplasm /cancer transplantation; neoplastic process; organ culture; preneoplastic state; somatotropin

DESCRIPTION (provided by applicant): Substantial progress has been made in the prevention and treatment of breast cancer by developing new agents that target signal transduction pathways such as those stimulated by estrogen or HER2. Unfortunately, many patients' tumors become independent of these pathways indicating an urgent need to identify alternative targets. Recent clinical trials and laboratory based studies indicate that the growth hormone/insulin-like growth factor-I (GH/IGF) pathway may be important in breast cancer development. We have discovered that the Spontaneous Dwarf rat (SDR), which lacks GH due to a missense mutation in its GH gene, is nearly refractory to mammary cancer. Our hypothesis is that down regulation of the GH/IGF axis substantially retards initiation as well as promotion/progression stages of mammary carcinogenesis. Our first aim is to determine if the SDR can be made susceptible to carcinogens by treatment with GH or IGF-I administered to the SDR in vivo or to SDR mammary gland organ cultures. We also propose to compare the profile of mammotropic hormones in serum and their receptors in the mammary glands of SDRs and wild-type littermates. The second aim is to evaluate the role of the GH/IGF axis at initiation and promotion/progression stages of carcinogenesis. We will compare the SDR, the SDR treated with either GH or IGF-I, and wild-type littermates with respect to apoptosis and proliferation within the mammary gland, in response to carcinogenic insult. We will evaluate whether preneoplastic lesions develop in the mammary glands of carcinogen-exposed SDRs and examine advanced cancers for GH and IGF-I receptors. Mammary tumor transplant experiments are proposed to determine if advanced cancers are GH or IGF-I dependent. The third aim is to study the role of GH in a novel mouse model of estrogen independent mammary cancer. We will cross the C3(1)/Tag mouse, which spontaneously develops estrogen independent mammary cancers, with either the GH receptor/binding protein knockout mouse or the GH antagonist mouse. The long-term goals for this project are to determine the suitability of the GH/IGF axis as a novel target for the development of chemopreventative and/or therapeutic agents. Results from these studies could be rapidly translated to the clinic since a GH antagonist (pegvisomant) is currently in phase III trials for the treatment of acromegaly.

描述（由申请人提供）：通过开发靶向信号转导通路（如雌激素或HER2刺激的信号转导通路）的新药，在乳腺癌的预防和治疗方面取得了实质性进展。不幸的是，许多患者的肿瘤变得独立于这些途径，这表明迫切需要确定替代靶点。最近的临床试验和基于实验室的研究表明，生长激素/胰岛素样生长因子- 1 （GH/IGF）途径可能在乳腺癌的发展中起重要作用。我们发现，由于生长激素基因错义突变而缺乏生长激素的自发性矮鼠（SDR）对乳腺癌几乎是难治的。我们的假设是，GH/IGF轴的下调实质上延缓了乳腺癌发生的起始和促进/进展阶段。我们的第一个目标是确定SDR是否可以通过对SDR体内或SDR乳腺器官培养的GH或igf - 1进行治疗而对致癌物敏感。我们还建议比较SDRs和野生型幼崽血清中促乳激素及其乳腺受体的分布。第二个目的是评估GH/IGF轴在癌变起始和促进/进展阶段的作用。我们将比较SDR、GH或igf - 1处理的SDR和野生型幼崽在癌变损伤后乳腺内的细胞凋亡和增殖情况。我们将评估暴露于致癌物质的sdr患者的乳腺是否会发生癌前病变，并检查晚期肿瘤的生长激素和igf - 1受体。乳腺肿瘤移植实验被提出以确定晚期癌症是否依赖GH或IGF-I。第三个目的是研究生长激素在雌激素不依赖型乳腺癌小鼠模型中的作用。我们将C3(1)/Tag小鼠与生长激素受体/结合蛋白敲除小鼠或生长激素拮抗剂小鼠进行杂交，C3(1)/Tag小鼠会自发发展为不依赖雌激素的乳腺癌。该项目的长期目标是确定GH/IGF轴作为开发化学预防和/或治疗药物的新靶点的适用性。由于生长激素拮抗剂（pegvisomant）目前正处于治疗肢端肥大症的III期试验，这些研究的结果可以迅速转化为临床。