Defining the role of aberrant O-linked glycosylation in breast cancer

蛋白质是由细胞DNA中包含的基因编码的，表达的蛋白质模式称为蛋白质组。然而，在细胞表面发现的绝大多数蛋白质以及在细胞内发现的许多蛋白质都携带被称为糖链的糖。这些糖，以及细胞表达的其他分子携带的糖被称为糖素。一种蛋白质可以被不同的糖链修饰，这将影响它的功能以及它如何与同一细胞和不同细胞上的其他成分相互作用。因此，糖糖在许多生物过程中扮演着关键的角色，并且可能比蛋白质组更复杂。糖聚糖在许多疾病中发挥作用，在癌症中，附着在蛋白质上的葡聚糖往往不同于正常细胞表达的附着在同一蛋白质上的多糖。由于这会改变蛋白质和细胞的功能，所以在癌症中观察到的糖基化的变化可以影响肿瘤的发展和进展。我们一直在研究一种特殊的糖基化类型，O-连接，这种类型的糖基化的变化发生在90%的乳腺癌中。我们假设，这种常见和持续的变化在乳腺癌的发生和发展中发挥了作用。我们已经发现，在乳腺癌中发生的这些附着在蛋白质上的葡聚糖的变化是由于催化糖链加到蛋白质中的酶(称为糖基转移酶)的表达的变化。两种特殊的糖蛋白MUC1和骨桥蛋白与乳腺癌有关，与正常细胞相比，当癌细胞表达这些蛋白时，这些蛋白携带的糖链会发生变化。MUC1是一种大的糖蛋白，它可以与较小的表面蛋白如EGFR相互作用，并影响这些分子如何向细胞核发出信号，从而控制基因的表达。在这个项目中，我们的目标是建立一个特定的糖基转移酶在乳腺癌中过度表达的机制，它可以影响乳腺癌的发展。为了实现这一目标，我们将使用我们开发的小鼠模型，在该模型中，糖基转移酶的过度表达会导致乳腺肿瘤比对照组更早发展。我们还将研究MUC1和骨桥蛋白糖链的变化在乳腺癌进展中的作用。我们将研究MUC1上的O-连接多糖如何改变其与EGFR的相互作用，以及对基因转录的影响。将确定连接到活性和非活性骨桥蛋白上的O-连接的多糖。通过控制糖基转移酶的表达，我们将改变骨桥蛋白上附着的多糖，并确定对其刺激转移能力的影响。来自该项目的数据将深入了解控制癌症发生和进展的一些机制，从而确定新的潜在治疗靶点。

Proteins are encoded by genes contained within the DNA of the cell and the pattern of proteins expressed is known as the proteome. However, the vast majority of proteins found on the cell surface and many found within the cell carry sugars known as glycans. These sugars, and sugars carried on other molecules expressed by the cell are known as the glycome. A single protein can be modified by different glycans, which will affect its function and how it interacts with other components in the same cell and on different cells. Thus the glycome plays a key role in many biological processes and can be more complex then the proteome.Glycans play a role in many diseases and in cancer the glycans attached to proteins are often different to those attached to the same protein expressed by normal cells. As this can alter the way proteins and therefore cells function, changes in the glycosylation observed in cancer can influence tumour development and progression.We have been studying one particular type of glycosylation, O-linked, and changes in this type of glycosylation occurs in >90% of breast cancers. We hypothesise that such a common and consistent change plays a role in the development and progression of breast cancer. We have found that the changes in these glycans attached to proteins that occur in breast cancer are due to changes in the expression of enzymes (known as glycosyltransferases) that catalyse the addition of the glycans to the protein. Two particular glycoproteins known as MUC1 and osteopontin are associated with breast cancer and the glycans carried on these proteins are changed when they are expressed by cancer compared to normal cells. MUC1 is a large glycoprotein which can interact with smaller surface proteins for example EGFR, and affect how these molecules signal to the nucleus and so control gene expressionIn this project we aim to establish the mechanism by which a particular glycosyltransferase that is over-expressed in breast cancer can influence the development of mammary cancer. To achieve this aim we will use a murine model developed by us where over-expression of the glycosyltransferase causes mammary tumours to develop earlier than the controls. We will also investigate the role changes in the glycans of MUC1 and osteopontin have on the progression of breast cancer. We will investigate how the O-linked glycans on MUC1 alter its interaction with EGFR and what the consequences are for gene transcription. The O-linked glycans attached to active and inactive osteopontin will be determined. By manipulating the expression of glycosyltransferases we will change the glycans attached to osteopontin and determine the influence on its ability to stimulate metastasis.The data coming from this project should give an insight into some of the mechanisms controlling cancer development and progression and therefore identify new potential therapeutic targets for the treatment of cancer.