HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM

内分泌乳房激素雌激素和黄体酮不仅正常 而且还有乳房肿瘤性生长。潜在的机制很差 理解但无疑涉及对组织中介的监管 例如胰岛素样生长因子(IGF)，它们是促进 正常乳腺细胞在体外，并已被牵连在 这些细胞的不受控制的肿瘤性生长。使用缓释塑料 植入原位治疗小鼠乳腺的小区域，我们 最近证实了IGF与雌激素的局部协同刺激作用 导管生长。在使用的剂量下，无论是雌激素还是IGF-I 刺激了腺体。这种效果，伴随着丰富的 腺体中的IGF-I信息，有力地证明了IGF-I是正常的， 局部作用的导管乳房钼靶。 我们现在建议研究胰岛素样生长因子系统的局部激素调节。 并开发了一种全新的体内研究系统来做到这一点。 使用含有抗雌激素或抗孕酮的缓释植入物 消融同源受体的作用；局部阻断类固醇- 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 生长因子调控是理解腺体调控的关键 在正常和病态的情况下。事实上，这一点是 本提案所回应的RFA的重点。清晰的切割能力 我们的系统将类固醇/生长因子的调节 在初步研究中描述了直截了当、毫不含糊的方式。 因此，该系统承诺直接回答许多问题，包括 雌激素和孕激素对正常范围内IGF系统的调节， 癌前病变和肿瘤性腺体。 这一新方法将用于研究雌激素和黄体酮。 IGF-I、IGF-II、IGF-1和IGF-2受体以及 体内某些IGF结合蛋白。预计将公布的细节 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，从上述实验中推断将进一步 通过植入突变形式的免疫球蛋白来扰乱正常活动和 取消本地操作的掩码。我们将基因表达与良好的- 腺体内明确的、生物相关的终点(导管生长 相对于抑制)，意味着关于功能的强烈推论 胰岛素样生长因子系统的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.