Metastasis is a major cause of morbidity in breast cancer patients so a deeper understanding of the mechanisms underlying this process is of obvious importance. We have identified a set of proteins, called Id proteins, which facilitate the early stages of breast cancer cell growth in the lung metastatic site and whose overexpression in breast cancer is associated with the ability of these cells to remain in an undifferentiated, "stem-like" state. These proteins appear to antagonize the mesenchymal, migratory state that allow cells in the primary tumor to initially break off from the tumor bulk and travel through the blood stream. Indeed, we postulate here that the Id proteins allow for breast cancer cells in circulation to reacquire an epithelial-like fate whereby growth and colonization are facilitated. In this proposal we will explore the mechanism whereby the Id proteins induce this "recolonization" phenotype by identifying the proteins that are affected by Id directly and indirectly. This section will be a collaboration with Joan Massague and Filippo Giancotti. In addition , we will identify the key mechanisms whereby Id itself is upregulated during the metastatic process under the control of the TGF? growth factor. This section will be a collaboration with Joan Massague. Finally, having identified a small molecule the affects the ability of Id proteins to associate with their target proteins, we will attempt to further develop this novel class of compounds for anti-metastatic efficacy in pre-clinical models. This section will be a collaboration with Neal Rosen, Larry Norton and Joan Massague.
In this proposal we characterize a set of proteins, called Id proteins, that are highly expressed in breast cancer cells and are required for their ability to seed the growth in the lung, a key site of metastatic spread and a significant clinical problem. We have shown that these proteins, not normally present in the adult but abundant in the early embryo, exert in tumors the precise effect they due during early fetal formation, namely the stimulation of growth of stem-like cells important for early colonization and long-term growth potential. We have identified targets for the Id proteins that likely mediate its effects and will test the importance of these proteins in cells grown in the laboratory and in animal models of breast cancer. We have also identified a key growth factor that stimulates Id protein expression in breast cancer and will further characterize its precise mechanism of action. Finally, we have identified a small, drug-like molecule that severely attenuates the ability of the Id proteins to work and shows evidence of inhibiting primary breast cancer growth in living animals. These molecules will be further analyzed for their anti-metastatic activity in mouse models and a more complete description of its biological activity is sought. This compound is among the first to antagonize the ability of a protein to interact with its partner and may facilitate the identification of similar molecules that will likely have broad clinical application.
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