Early events of carcinoma induced by ErbB receptors

描述（由申请人提供）：我们知道癌症的发病机制始于增生性病变，其中一些进展为恶性，而另一些保持良性。区分病变的分子特征在很大程度上是未知的。这部分是由于我们缺乏对启动上皮细胞体内转化的分子机制的理解。生长控制的丧失和上皮结构的破坏被认为是癌症的最早期事件。然而，我们不知道癌基因如何协调解除生长控制和结构，启动上皮细胞在体内的转化。ErbB受体酪氨酸激酶家族的癌基因可以在体内启动上皮细胞的转化。然而，理解ErbB家族的不同成员如何转化上皮细胞一直是一个挑战，因为它们通过在它们之间形成同源和异源二聚体来发挥作用，这使我们剖析特定ErbB二聚体所起作用的能力变得复杂。我们已经开发了一种新的方法来控制ErbB受体的二聚化，这将使我们能够激活正常上皮细胞中选择的特定受体二聚体。我们还采用了一种细胞培养方法来产生三维的，极化的，生长停滞的上皮细胞，这些上皮细胞与体内导管内衬细胞具有几种特性。这两种方法的结合为我们提供了新的和强大的工具，以了解ErbB受体转化生长停滞，极化上皮细胞的分子机制。利用我们独特的系统，我们将激活ErbB受体二聚体的各种组合，以（1）研究特异性ErbB二聚体诱导三维乳腺上皮腺泡样结构中不受控制的增殖和结构丧失的能力，并鉴定对该过程至关重要的信号传导途径（2）鉴定不同ErbB同源物的机制，和异源二聚体影响调节上皮细胞极性的蛋白质的定位和功能，和（3）确定ErbB二聚体破坏细胞极性的能力和它们在生长停滞中重新启动增殖的能力之间的关系，极化上皮细胞特别重要的是，我们有能力发现新的分子机制参与启动癌症，并确定新的和特定的目标，用于治疗ErbB阳性肿瘤患者。

DESCRIPTION (provided by applicant): We know that pathogenesis of cancer begins as hyperplastic lesions, some of which progress to malignancy while other remain benign. The molecular features that differentiate lesions are largely unknown. This is in part due to lack of our understanding of the molecular mechanisms that initiate transformation of epithelial cells in vivo. Loss of growth control and disruption of epithelial architecture are thought to be earliest events in cancer. However, we do not understand how oncogenes coordinately deregulate growth control and architecture to initiate transformation of epithelial cells in vivo. Oncogenes of the ErbB receptor tyrosine kinase family can initiate transformation of epithelia in vivo. However, it has been a challenge to understand how different members of the ErbB family transform epithelial cells because they function by forming homo- and heterodimers amongst themselves, which complicates our ability to dissect out the role played by specific ErbB dimers. We have developed a novel method to control dimerization of ErbB receptors that will allow us to activate specific receptor dimers of choice in normal epithelial cells. We have also adapted a cell culture method to generate three-dimensional, polarized, growth-arrested epithelial cells that share several properties with cells lining the ducts in vivo. Combination of these two approaches provides us with novel and powerful tool to understand the molecular mechanisms by which ErbB receptors transform growth-arrested, polarized epithelial cells. Using our unique system, we will activate various combinations of ErbB receptor dimers to (1) investigate the ability of specific ErbB dimers to induce uncontrolled proliferation and loss of architecture in 3D mammary epithelial acini-like structures and identify the signaling pathways critical for this process (2) identify the mechanisms by which different ErbB homo- and heterodimers affect localization and function of proteins that regulate epithelial cell polarity, and (3) determine the relationship between the ability of ErbB dimers to disrupt cell polarity and their ability to re-initiate proliferation in growth-arrested, polarized epithelial cells. Of particular importance is our capability to uncover novel molecular mechanism involved in initiation of carcinoma and also to identify novel and specific targets for treating patients with ErbB-positive tumors.