HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM

内分泌乳腺激素雌激素和孕激素不仅正常 还有乳腺肿瘤生长。基础机制薄弱 理解但无疑涉及组织中介机构的监管 例如胰岛素样生长因子 (IGF)，它是有效的有丝分裂原 正常乳腺细胞在体外并与 这些细胞不受控制的肿瘤生长。使用缓释塑料 我们通过植入物对小鼠乳腺的小区域进行原位治疗 最近证明 IGF 与雌激素的局部协同作用可刺激 导管生长。在使用的剂量下，雌激素或 IGF-I 均不单独使用 刺激了腺体。这种效应，以及丰富的存在 腺体中的 IGF-I 信息是 IGF-I 正常的有力证据， 局部作用的导管乳腺原。 我们现在建议研究 IGF 系统的局部激素调节 并为此开发了一种全新的体内研究系统。 使用含有抗雌激素或抗孕激素的缓释植入物 消除同源受体的作用；类固醇的局部破坏 依赖的基因表达可以使用标准方法检测，例如 Northern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 在正常和病理情况下。事实上，这一点就是 该提案所回应的 RFA 的焦点。清除能力 我们的系统将类固醇/生长因子调节联系起来 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以下方面的许多问题： 雌激素和孕激素调节 IGF 系统正常范围内， 癌前腺体和肿瘤腺体。 这种新方法将用于研究雌激素和黄体酮 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。特定生长调节功能 由上述实验推断的结合蛋白将进一步 通过植入突变形式的 IGI 来扰乱正常活动和 揭开本地行动的面纱。我们将基因表达与良好联系起来的能力 腺体内定义的生物学相关终点（导管生长 与抑制），意味着关于功能的强烈推论 IGF 系统激素调节的重要性即将到来。

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.