HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM

乳房 IGF 系统的荷尔蒙调节

• 批准号: 2149390
• 负责人: CHARLES W DANIEL
• 金额: $ 17.83万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2149390
• 关键词: binding proteins; cell growth regulation; estrogens; gene expression; hormone receptor; hormone regulation /control mechanism; implant; insulinlike growth factor; laboratory mouse; mammary gland; northern blottings; progesterone

The endocrine mammogens estrogen and progesterone drive not only normal but also neoplastic mammary growth. Underlying mechanisms are poorly understood but no doubt involve the regulation of tissue intermediaries such as Insulin-like Growth Factors (IGFs) which are potent mitogens for normal mammary cells in vitro and have been implicated in the uncontrolled, neoplastic growth of these cells. Using slow-release plastic implants to treat small regions of the mouse mammary gland in situ, we recently demonstrated localized synergy of IGF with estrogen to stimulate ductal growth. At the doses used, neither estrogen or IGF-I alone stimulated the gland. This effect, along with the presence of abundant IGF-I message in the gland, is strong evidence that IGF-I is a normal, locally-acting ductal mammogen. We now propose to investigate local hormonal regulation of the IGF system and have developed a completely novel in vivo research system to do so. Slow-release implants containing antiestrogen or antiprogesterone are used to ablate cognate receptor action; localized disruption of steroid- dependent gene expression is detectable using standard methods such as Northern hybridization analysis. The capacity to relate steroid action to growth factor regulation is crucial to understanding glandular regulation in normal and pathological circumstances. Indeed, this single point is the focus of the RFA to which this proposal responds. The clearcut capability of our system to link steroid/growth factor modulation in a straightforward, unambiguous manner is described in preliminary studies. This system therefore promises direct answers to many questions concerning estrogen and progesterone regulation of the IGF system within the normal, preneoplastic and neoplastic gland. This new approach will be used to investigate estrogen and progesterone regulation of IGF-I, IGF-II, IGF type 1 and type 2 receptors, as well as certain IGF binding proteins in vivo. It is expected that the details of hormonal regulation of paracrine and negative feedback regulation of IGF action will come into focus. Growth-regulatory functions for specific binding proteins, inferred from the above experiments will be further defined by implanting mutant forms of IGI to perturb normal activity and unmask local actions. Our ability to relate gene expression to well- defined, biologically relevant end points within the gland (ductal growth versus inhibition), means that strong inferences concerning the functional importance of hormonal regulation of the IGF system will be forthcoming.

内分泌乳腺雌激素和孕酮不仅正常 但也是肿瘤的乳腺生长。潜在机制很差 理解但毫无疑问涉及组织中介机构的调节 例如胰岛素样生长因子（IGF） 正常乳腺细胞体外，与 这些细胞的肿瘤生长不受控制。使用缓释塑料 植入物治疗原位小鼠乳腺的小区域，我们 最近证明了IGF与雌激素的局部协同作用以刺激 导管生长。在使用的剂量下，均不单独使用雌激素或IGF-I 刺激腺体。这种效果，以及丰富的存在 腺体中的IGF-I消息是有力的证据表明IGF-I是正常的， 局部作用导管性乳腺癌。 现在，我们建议研究IGF系统的局部激素调节 并开发了一种完全新颖的体内研究系统。 使用含有抗雌激素或抗脂蛋白的慢释植入物 消融同源受体作用；类固醇的局部破坏 使用标准方法（例如 北部杂交分析。将类固醇作用与 生长因子调节对于理解腺体调节至关重要 在正常和病理环境中。确实，这个点是 该提案回应的RFA的重点。清除功能 我们的系统将类固醇/生长因子调节连接 初步研究中描述了直接，明确的方式。 因此，该系统有望直接回答有关许多有关的问题 雌激素和孕激素调节在正常状态下IGF系统 肿瘤和肿瘤腺。 这种新方法将用于研究雌激素和孕酮 IGF-I，IGF-II，IGF 1型和2型受体的调节，以及 体内某些IGF结合蛋白。预计的细节 旁分泌的激素调节和IGF的负反馈调节 行动将成为焦点。特定的生长调节功能 结合蛋白，从上述实验推断出的结合蛋白将进一步 通过植入IgI突变形式来扰动正常活动和 揭露本地行动。我们将基因表达与良好相关的能力 定义，腺体内的生物学相关端点（导管生长 与抑制作用），意味着有关功能的强烈推论 IGF系统的激素调节的重要性将即将到来。