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Regulation of the EGF family of receptor tyrosine kinases in human cancers.

Our laboratory has focused on the EGF (ErbB) family of receptor tyrosine kinases known to be important in proliferation, survival, and differentiation of epithelial cells and in malignant progression of several cancers. Our overall goal has been to identify the biochemical mechanisms underlying receptor activation and regulation and to directly translate the basic science findings into development of effective prognostic markers and improved therapeutics for cancer patients. One of these novel products, called Herstatin, is a naturally occurring secreted inhibitor of the EGF receptor. The second novel product, p95HER-2, a truncated form of the receptor, appears to be important in malignant progression of breast cancer and its detection may be used to predict outcome in early stage breast cancer.

Our lab discovered and characterized two novel alternative products of the Human EGF Receptor-2 gene, the HER-2/neu gene that may impact oncogenesis. One of these novel products, called Herstatin, is generated from intron retention in an alternative HER-2 transcript, which is expressed in developing tissues. Herstatin encodes a secreted protein that contains part of the HER-2 receptor itself and a novel domain encoded by the retained. This unique ligand, binds to the ectodomain of HER-2 and the EGF receptors and blocks their activation. Our ultimate goal is to define the function of Herstatin in the regulation of receptor signaling pathways that culminate in growth or cell death and to evaluate potential utility as a cancer therapeutic.

The other alternative product of HER-2, we are investigating is created by proteolytic shedding of the extracellular domain of the receptor. The extracellular domain of HER-2 is released from the surface of breast carcinoma cells into the media generating a constitutively active kinase, p95HER-2, associated with the tumor cell. We recently found high levels of the truncated p95HER-2 in tumor tissue breast predicted worse outcome for HER-2 positive breast cancer patients.
 

Recent Publications:

1. Staverosky JA, Muldoon LL, Guo S, Evans AJ, Neuwelt EA, Clinton GM. Herstatin, an autoinhibitor of the epidermal growth factor receptor family, blocks the intracranial growth of glioblastoma. Clin Cancer Res. 11(1):335-40 (2005).

2. Shamieh L.S., Evans A.J., Denton M.C., and Clinton, G.M. Receptor binding specificites of Herstatin and its intron 8-encoded domain. FEBS Letters In press (2004).

3. Chatterji A., Ochoa W., Shamieh L., Salakian S.P., Clinton G., Ghosh P., Lin T., and Johnson J.E. Chemical conjugation of heterologous protein on the surface of cowpea mosaic virus. Conjugate Chemistry In press (2004).

4. Jhabvala-Romero, F., Evans, A., Guo, S., Denton, M., and Clinton, G.M. Herstatin inhibits Heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2. Oncogene 50: 8178-8176 (2003).

5. Justman, Q.A., and Clinton, G.M. Herstatin, an autoinhibitor of the human epidermal growth factor receptor 2 tyrosine kinase, modulates epidermal growth factor signaling pathways resulting in growth arrest. J. Biol. Chem. 277(23): 20618-24 (2002).

6. Molina, M.A., Saez, R., Ramsey, E.E., Garcia-Barchino, M.J., Rojo, F., Evans, A.J., Albanell, J., Keenan, E.J., Lluch, A., Garcia-Conde, J., Baselga, J., and Clinton, G.M. NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin. Cancer Res. 8: 347-53 (2002).