GROWTH FACTOR INDUCED BREAST CANCER

生长调节肽的活化表达是生长调节的标志。 肿瘤形成 转化生长因子-α的显著诱导 （TCF α）在广泛的人类和动物肿瘤中，以及在 转化细胞系就是一个很好的例子。 EGF受体 TGF-α是一种有效的上皮细胞有丝分裂原， 间充质细胞 它还调节细胞分化和迁移， 它与血管生成、伤口愈合和肝脏 再生 为了探索激活的 我们建立了转基因小鼠品系， 多种组织中的生长因子。 一个重要的后果是， 乳腺癌的发展与高发病率在哺乳期后 女性 TGF α在泌乳期乳腺中的靶向表达 在乳清酸性蛋白（WAP）启动子的控制下， 可移植的癌，其中一个转移到肺。 在 在经产女性中，发现局灶性肿瘤与大 增生性肺泡（HAN）的数量，其起源被认为是 我们观察到TGF α阻断了，或者至少部分阻断了 抑制，正常的破坏乳腺年底 泌乳（退化）。 根据这些不同的结果，我们 假设未消退的腺体构成癌前病变。 这些细胞中的一部分最终形成肿瘤， 更多的基因事件 我们建议进一步研究有关机制， 在这些独特的模型中，TGF α通过其诱导乳腺癌。 我们 具体目的是：（1）表征分子特征， 表达失调诱导的乳腺肿瘤分子表型 2）研究WAP-1表达的机制。 TGF α转基因启动乳腺癌的发展;和3） 探索TGF α转基因小鼠提供模型的可能性， 用于研究乳腺肿瘤进展。 在Aim I中，我们将 将不同转基因的表达模式和水平相关联， 并将这些结果与所产生的 肿瘤，部分集中在如何肿瘤诱导多肽 生长因子影响类固醇激素的反应性， 肿瘤的 此外，我们将寻找扩增和/或激活 特定候选基因（例如EGF-R和new）的表达，我们 将为其他成员开发新的转基因模型， 配体/受体信号传导家族，在目标II中，我们将进一步探索 TGF α对发育的影响 特别关注的可能性， 阻断正常的凋亡事件。 我们还将研究 一种不可切割的转化生长因子α原 在目标III中，我们将进一步 表征TGF α诱导的HAN以确定它们是否提供 肿瘤进展的模型，我们将利用逆转录病毒 标签方法来识别可能与TGF α合作的基因 乳腺肿瘤发生

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.