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Molecular Action of a Potential Tumor Suppression in Mammary Carcinogenesis

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Annual rept. 14 Apr 2005-13 Apr 2006

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ErbB family of growth factor receptors ErbB1-4 are critically involved in the derivation of certain mammary cancers 1-3. Among them, ErbB2Her2 is most notable as overexpression or amplification of this gene is found in approximately 30 of human breast cancers and people with these ErbB2-overexpressing tumor have a shorter time to relapse and lower overall survival rate than patients whose tumors do not overexpress ErbB2 4-9. Since ErbB2 activity plays such an important role in development of breast cancer, it is important to understand the regulatory mechanisms by which mammary cells maintain the proper intensity and specificity of ErbB2-generated signaling. ErbB receptors promote tumor progression by sending oncogenic signals into cells through its cytoplasmic signaling domain 10-14. In this regard, we discovered that the signaling domain of ErbB2 interacts with Tid1 protein and that the increased expression of this protein in ErbB2-overexpressing breast cancer cells promotes ubiquitinization and proteosomal degradation of ErbB2 resulting in potent inhibition of ErbB2-dependent intracellular signaling. We hypothesize that Tid1 act as a tumor suppressor in breast tumorigenesis associated with ErbB2 malfunction. The proposed study should verify our hypothesis and test the therapeutic potential of Tid1 in treating tumor overexpressing ErbB2. To investigate the function and molecular action of Tid1 gene as a tumor suppressor in the development of breast cancer, we propose 1 to investigate Tid1s role in the onset and progression of breast tumor using in vivo animal model 2 Further explore the functional role of Tid1 on both signaling events and functional responses mediated by ErbB2 in breast cancer cells 3 identify structural domains in Tid1 required for recognition and inhibition of ErbB2 signaling.

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  • Medicine and Medical Research

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