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Glyolysis, IRS-2 and Metastatic Breast Cancer
Tumor Cell Biology II
The metabolism of breast cancer cells differs significantly from that of normal cells: invasive and metastatic breast carcinoma cells are characterized by high rates of glycolysis, as opposed to oxidative phosphorylation in normal cells. In fact, such tumor cells prefer glycolysis over oxidative phosphorylation, even in the presence of oxygen. This phenomenon, known as aerobic glycolysis, was first described in the 1920s and it has been "re-discovered" as scientists establish the central role that glycolysis plays in driving tumor progression. Given that aerobic glycolysis is a distinguishing characteristic of invasive and metastatic breast cancer cells, it is a prime target for diagnostic imaging and therapy. To exploit glycolysis for the clinical management of breast cancer, however, much more needs to be learned about how it is induced and sustained in breast tumors. This Komen proposal is a pilot study based on a novel and innovative hypothesis that integrates glycolysis with the insulin receptor substrate (IRS) proteins, which are key signaling intermediates for multiple surface receptors. Recent studies have revealed an exquisite specificity among IRS proteins and breast cancer: IRS-2 promotes breast cancer invasion and metastasis and IRS-1 impedes this process. Moreover, our preliminary data indicate that IRS-2 expression is necessary for the enhanced rate of glycolysis observed in aggressive breast carcinoma cells and that it regulates the expression of a key glycolytic enzyme. Thus, we propose that IRS-2 is essential for the sustained increase in the rate of glycolysis that is characteristic of aggressive breast carcinoma cells. Three specific aims are proposed to address our hypothesis. In the first aim, the contribution of IRS-2 to aerobic glycolysis will be established using a mammary tumor model and human breast carcinoma cells. The second aim will address the mechanism by which IRS-2 regulates glycolysis and focus on the regulation of hexokinase II and the involvement of MAPK. The final aim tackles the important hypothesis that the established role of IRS-2 in promoting invasion and metastasis depends on its ability to regulate glycolysis. The proposed experiments will define a new mechanism for the regulation of aerobic glycolysis in breast cancer and they will facilitate clinical studies aimed at targeting glycolysis and IRS-2 for therapeutic intervention.
The unfortunately high rate of mortality associated with breast cancer results mostly from the primary tumor spreading to lymph nodes and other organs such as bone, lung and brain. This process of tumor spread or "metastasis" must be understood better so that more effective therapies can be developed. Such therapies need to distinguish between normal tissue and more aggressive tumor cells. Interestingly, one of the most distinguishing characteristics of breast tumor cells, especially cells that are invasive and metastatic, is that they consume enormous amounts of glucose compared to normal and less aggressive cells in a process referred to as "glycolysis". The voracious appetite that these breast tumor cells have for glucose provides them with the energy they need to grow and metastasize. Glycolysis is actually the basis for a very powerful diagnostic imaging process (PET) that can detect primary breast tumors and their metastases. Moreover, tumor cells die if glycolysis is inhibited. For this reason, drugs are being developed that block this key process. A major problem is that we don?t understand how glycolysis is controlled in breast tumor cells. This Komen proposal addresses this issue. We postulate based on our preliminary data that a specific protein that is known to promote metastasis plays an important role in controlling glycolysis. This protein, which is referred to as insulin receptor substrate-2 (IRS-2), is expressed preferentially in more aggressive breast tumors and loss of its expression prevents metastasis in a mouse model. Loss of IRS-2 expression reduces glycolysis in breast tumor cells significantly and makes them less aggressive. Given these findings, we propose to obtain definitive evidence to link IRS-2 to glycolysis in breast tumor cells using both a mouse model and cells isolated from human breast tumors. We also propose to explain how IRS-2 controls glycolysis. Our data suggest that IRS-2 regulates the expression an enzyme that is essential for glycolysis. Finally, we plan to test our hypothesis that the reason that IRS-2 promotes breast cancer metastasis is because it regulates glycolysis. Our proposed experiments will define a new mechanism that explains how breast tumor cells invade and metastasize. The information obtained should be of immediate use to facilitate the development of targeted drugs that block both glycolysis and IRS-2 in breast cancer.