GROWTH FACTOR INDUCED BREAST CANCER

生长调节肽的激活表达是一个标志 肿瘤。转化生长因子-α的显著诱导 (TCFpha)在广泛的人类和动物肿瘤中，以及在 转化的细胞系就是一个很好的例子。表皮生长因子受体的成员 配体家族，TGFpha是一种有效的上皮细胞和 间充质细胞。它还调节细胞分化和迁移， 它还与血管生成、伤口愈合和肝脏有关。 再生。探讨激活的病理后果 我们建立了过表达TGFα的转基因小鼠系 多种组织中的生长因子。一个重要的后果是 哺乳期后高发乳腺癌的发生发展 女性。肿瘤生长因子α在哺乳期乳腺组织中的靶向性表达 在乳清酸性蛋白(WAP)启动子的控制下产生 可移植癌，其中一例转移至肺。在……里面 经产女性，局灶性肿瘤与大的 增生性肺泡数(HANS)，推测其来源 根据我们的观察，转化生长因子α阻断了，或至少部分地 抑制，乳腺末的正常破坏 哺乳(复活)。鉴于这些不同的结果，我们 假设未退化的腺体构成癌前病变。 这些细胞中的一小部分最终会形成肿瘤，原因是 额外的遗传事件。我们建议进一步研究这些机制。 在这些独特的模型中，TGFpha通过这种方式诱导乳腺癌。我们的 具体目标是：(1)表征分子表征 基因表达失调性诱导的乳腺肿瘤分子表型 2)探讨WAP-α表达的机制(S)。 转化生长因子α转基因启动乳腺癌的发生； 探索转化生长因子α转基因小鼠提供模型的可能性 用它来研究乳房的肿瘤进展。在Aim I中，我们将 不同转基因的表达模式和水平相关联， 并将这些结果与结果的不同特征进行比较 肿瘤，部分集中在多肽如何诱导肿瘤 生长因子影响所致的类固醇激素反应性 肿瘤。此外，我们将查找放大和/或激活 表达特定的候选基因(例如EGF-R和new)，以及WE 将为世界卫生组织其他成员开发新的转基因模型 配体/受体信号家族，在AIM II中，我们将进一步探索 肿瘤生长因子α在发育过程中对发育和退化的影响 特别关注的是它是否有可能 阻断正常的细胞凋亡事件。我们还将检查活动 一种不可切割形式的原转化生长因子α。在AIM III中，我们将进一步 表征TGFpha诱导的HANs，以确定它们是否提供 一个肿瘤进展的模型，我们将利用逆转录病毒 标记方法识别可能与肿瘤生长因子α协同作用的基因 乳房肿瘤的发生。

Activated expression of growth regulating peptides is a hallmark of neoplasia. The conspicuous induction of transforming growth factor-alpha (TCFalpha) in a wide array of human and animal tumors, as well as in transformed cell lines, is a case in point. A member of the EGF receptor ligand family, TGFalpha is a potent mitogen for epithelial and mesenchymal cells. It also regulates cell differentiation and migration, and it has been implicated in angiogenesis, wound healing and liver regeneration. To explore the pathological consequences of activated TGFalpha expression we created lines of transgenic mice that overexpress the growth factor in multiple tissues. A significant consequence was the development of breast cancer with high incidence in postlactational females. Targeted expression of TGFalpha in the lactating mammary gland under the control of the whey acidic protein (WAP) promoter produced transplantable carcinomas, one of which metastasized to lung. In multiparous females, focal tumors were found in association with large number os hyperplastic alveolar (HANs) the origin of which is suggested by our observation that TGFalpha blocked, or at least partially inhibited, the normal destruction of mammary glands at the end of lactation (involution). IN light of these various results, we hypothesize that not-regressed glands constitute preneoplastic lesions. Cells in a fraction of these eventually form tumors as a result of additional genetic events. We propose to further examine the mechanisms by which TGFalpha induces breast cancer in these unique models. Our Specific Aims are to: (1) characterize the molecular characterize the molecular phenotypes of breast tumors induced by deregulated expression of TGFalpha; 2) investigate the mechanism(s) by which expression the WAP- TGFalpha transgene initiates the development of breast cancer; and 3) explore the possibility that TGFalpha transgenic mice provide a model with which to study neoplastic progression in breast. In Aim I, we will correlate patterns and levels of expression of the different transgenes, and compare these results with various characteristics of the resulting tumors, focussing in part on how neoplastic induction by a polypeptide growth factor influences steroid hormone responsiveness of resulting tumors. Additionally, we will look for amplification and/or activated expression of particular candidate genes (e.g. EGF-R and new), and we will develop new transgenic models for other members of the ligand/receptor signalling family, In Aim II, we will further explore effects of TGFalpha on the development on the development and regression of mammary glands with a particular focus on the possibility that it blocks the normal apoptotic events. We will also examine the activity of a non-cleavable form of proTGFalpha. In Aim III, we will further characterize the TGFalpha-induced HANs to determine whether they provide a model of neoplastic progression, and we will utilize a retroviral tagging approach to identify genes that might cooperate with TGFalpha breast tumorigenesis.