Regulation of erbB2 induced mammary gland cancer

描述：（从申请人的描述扫描）：成员的 表皮生长因子（EGF）受体家族与 乳腺癌的发展。特别感兴趣的是孤儿受体， erbB2（HER-2，p185，c-neu）。过度表达erbB 2的肿瘤对化疗没有反应。 抗激素治疗，往往比他们的非表达更具侵略性 同行证实erbB 2在肿瘤发生中的作用，转基因小鼠 过表达未激活形式的erbB 2， 腺体发展为转移性乳腺腺癌。虽然erbB 2过表达 肿瘤是非依赖性的，目前还不清楚激素环境是否 有助于他们的启蒙。使用双转基因小鼠方法，我们有 促黄体激素升高引起的卵巢过度刺激 导致erbB 2诱导的致癌转化显著加速 乳腺癌虽然肿瘤的发生在这些 在小鼠中，癌症促进必须在生命的早期发生，因为去除 卵巢在8周龄时对肿瘤诱导没有影响。因此虽然 激素刺激加速了早期事件的发生， 一个不依赖于癌症的致癌指令。这个过程可能会模仿 发生在乳腺癌患者身上的， erbB 2表达增加。虽然这些肿瘤通常 不依赖于激素，它们的启动可能发生在一种有益的激素中， 环境因此，了解这些早期事件是否至关重要， 这样我们就可以开始对 erbB 2诱导的乳腺癌从潜在的 他莫昔芬无法治疗的疾病。 在这一过程中确定具体的参与者无疑将揭示新的 可作为风险评估潜在标志的实体，以及 开发新治疗药物的特定目标。的 实验计划将首先涉及确定时间窗口 这种相互作用是加速肿瘤发展所必需的。在 此外，我们将确定卵巢激素对此负责， 相互作用和erbB 2功能的关键激活剂受到影响。最后我们 我建议检查乳腺组织基因表达谱的改变， 在erbB 2存在的情况下， 过度表达使用这种方法，我们将识别表达式中的变化 可能影响肿瘤发生级联反应进展的基因 由这两个因素引发的。这些研究将有助于制定新的 旨在了解分子间相互作用的可验证假设 激素和erbB 2诱导通路及其在乳腺癌中的后续作用 肿瘤发生

DESCRIPTION: (Scanned from the applicant's description): Members of the epidermal growth factor (EGF) receptor family have been implicated in the development of breast cancer. Of particular interest is the orphan receptor, erbB2 (HER-2, p185, c-neu). Tumors that overexpress erbB2 do not respond to anti-hormone therapy and tend to be more aggressive than their non-expressing counterparts. Confirming a role for erbB2 in tumorigenesis, transgenic mice that overexpress the unactivated form of erbB2 specifically in the mammary gland develop metastatic mammary adenocarcinomas. Although erbB2-overexpressing tumors are hormone-independent, it is unclear whether the hormonal milieu contributes to their initiation. Using a bitransgenic mouse approach, we have shown that ovarian hyperstimulation caused by elevated luteinizing hormone results in significant acceleration of erbB2-induced oncogenic transformation of the mammary gland. Although the initiation of tumors is accelerated in these mice, cancer promotion must occur very early in life, because removal of the ovaries at just 8 weeks of age has no impact on tumor induction. Thus, although early events are accelerated by hormonal stimulation, this rapidly progresses to an oncogenic directive that is hormone-independent. This process may mimic that which happens in human patients with breast cancer associated with increased expression of erbB2. Although these tumors are generally hormone-independent, their initiation likely occurred in a conducive hormone environment. Thus, is it essential to understand those early events mediated by hormonal input so that we can begin to develop an accurate picture of the natural progression of erbB2-induced mammary cancer from a potentially hormonally regulated state to one that becomes untreatable with tamoxifen. Identification of specific players in this process will undoubtedly reveal new entities that may serve as potential markers of risk assessment as well as specific targets for the development of new therapeutic agents. The experimental plan will first involve the identification of the window of time that this interaction is necessary for acceleration of tumor development. In addition, we will identify the ovarian hormones responsible for this interaction and key activators of erbB2 function that are affected. Lastly, we propose examining alterations in the gene expression profile of mammary tissue that occurs with ovarian hyperstimulation in the presence of erbB2 overexpression. Using this approach we will identify changes in the expression of genes that likely impact the progression of the tumorigenic cascade initiated by these two factors. These studies will allow the formulation of new testable hypotheses aimed at understanding the molecular interactions between hormone- and erbB2-induced pathways and their subsequent role in mammary tumorigenesis.