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    Research Grants Awarded

    Identifying Causes Of Aberrant Glycoprotein Processing And Altered Cell Adhesion In Breast Carcinomas.

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    Scientific Abstract A defining step in the progression of breast cancer to metastatic disease is the genesis of abnormal interactions between cells and the underlying basement membrane (BM). The constituents of the BM and their receptors are glycoproteins, modified by N- and O-linked glycosylation. Importantly, breast carcinoma cells undergo dramatic transformation in glycosylation pathways. In a notable example, we find that the aberrant glycosylation of the BM receptor dystroglycan (DG) disrupts its functions and prompts the invasiveness of breast cancers. However, the cause of altered glycosylation pathways in breast carcinomas and their consequence on cell-BM interactions are largely unknown. We hypothesize that aberrant cell signaling promotes the metastasis of breast carcinomas by transforming the glycosylation pathways and function of BM glycoproteins and receptors such as DG. Our objectives are to identify the signaling cues and molecules implicated in altered glycosylation of DG and to remedy the associated carcinoma phenotypes using pharmacological and genetic manipulations. Specifically, we shall: 1) Establish the molecular profile of breast carcinomas displaying defective glycosylation pathways. To accomplish this aim, we will determine the glycosylation state of DG in a defined collection of 51 breast carcinoma cell lines and analyze its potential association with the known genomic and transcriptional characteristics of these cells. These investigations will provide an understanding of the variables surrounding abnormal glycosylation pathways and possibly point to molecular relationships between DG function and known signaling or genetic defects in breast cancer cell lines and primary tumors. 2) Identify and manipulate candidate pathways that modulate DG processing and thereby cancer progression. This aim will focus on signaling pathways, glycosyltransferases and proteases which are known to modulate the functional glycosylation of DG. To date, our work has revealed that signals activated by transforming growth factor-beta (TGFb) lead to altered glycosylation of DG that resembles the defect in carcinoma cells. We propose to use pharmacological and genetic manipulations in order to identify the critical signaling mediators and abolish TFGb-induced aberrant glycosylation of DG. In addition, we will test for changes in expression or function of glycosyltransferases which are implicated in glycosylation pathway of DG. If discovered, we will then identify methods to restore the abnormalities of these enzymes by introducing the appropriate genes into the affected carcinoma cells. 3) Determine the potential of methods identified in Aim 2 to revert breast carcinoma cell behavior. To accomplish this aim, we will test the most robust methods identified in Aim 2 for their ability to remedy common phenotypes of breast carcinoma cells, including unresponsiveness to BM ligands, loss of polarity and enhanced invasiveness. A unique aspect of the approaches we propose is that they confront the root cause of cancer progression through restoring normal protein processing (glycosylation) pathways. The immediate impact of our studies is the discovery of pharmacological agents or genetic manipulations that remedy cellular glycosylation pathways and therefore rectify an array of carcinoma phenotypes resulting from dysfunction of BM receptors and ligands. Furthermore, association studies in 51 breast cell lines may yield novel prognostic measures based on the glycosylation status of DG in tumors from breast cancer patients. It is our belief and hope that the very same methods discovered in the course of this proposal will lead to new therapies aimed at blocking the devastating consequences of breast cancer metastasis.

    Lay Abstract:
    Public Abstract The mortality associated with breast cancer most often results from metastasis of the primary tumor to distal organs. A critical event in progression to metastatic disease is the migration of breast cancer cells through the underlying basement membrane (BM). The BM is a layer of secreted proteins (?ligands?) which provide structural support and contextual information to mammary cells by virtue of direct interaction with cell surface proteins (?receptors?). One defining feature of BM receptors and ligands is the presence of sugars which are added to the core protein through a process called ?glycosylation?. Remarkably, breast carcinomas undergo dramatic transformation in glycosylation pathways. In a notable example, we find that the aberrant glycosylation of the BM receptor dystroglycan (DG) can prompt invasiveness of breast cancers. However, the cause of altered glycosylation pathways in breast cancer and their consequence on cell-BM interactions and cancer progression remain largely unexplored. We hypothesize that signaling cues, activated in breast cancers, promote metastatic phenotypes by transforming the glycosylation pathways and function of BM ligands and receptors such as DG. Our objectives are to identify the signals and molecules implicated in altered glycosylation pathways and to remedy the associated carcinoma phenotypes using pharmacological and genetic manipulations. To this end, we will first identify the molecular signature of carcinomas that harbor dysfunctional DG by performing a systematic analysis in a defined set of 51 human breast cancer cell lines that have been classified into three subtypes. Subsequently, we will investigate candidate pathways implicated in abnormal glycosylation of DG in each carcinoma subtype. To date, our work has revealed one such pathway activated by a protein called ?transforming growth factor-beta? (TFGb). We propose to use pharmacological and genetic manipulations in order to abolish TFGb-induced perturbation of DG glycosylation in breast carcinomas. We will also test for potential alterations in enzymes that are implicated in glycosylation pathways of DG. We will then restore the abnormalities of these enzymes by introducing the appropriate genes into the affected breast carcinoma cells. Collectively, these investigations will identify at least one method, possibly multiple methods, to restore glycosylation of DG and perhaps other BM glycoproteins. Finally, we will test whether these methods can revert breast carcinoma behaviors including unresponsiveness to BM ligands, abnormal polarity and enhanced invasiveness. The immediate impact of our studies is the discovery of pharmacological agents or genetic manipulations that remedy cellular glycosylation pathways and therefore rectify an array of carcinoma phenotypes resulting from dysfunction of BM receptors and ligands. A unique aspect of the approaches we propose is that they confront the root cause of cancer progression through restoring normal protein processing (glycosylation) pathways. Furthermore, association studies in 51 breast carcinomas may yield novel prognostic measures based on the glycosylation status of DG in tumors from breast cancer patients. It is our belief and hope that the very same methods and tools discovered in the course of this proposal will lead to new therapies aimed at blocking the devastating consequences of breast cancer metastasis.