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Julie L. Boerner, Ph.D. |
RESEARCH INTERESTS:
My lab is interested in the role of two tyrosine kinases, the epidermal growth factor receptor (EGFR) and c-Src, in the progression of breast cancer. The EGFR is overexpressed in about 30% of breast tumors and often correlates with poor prognosis stemming from advanced disease. The EGFR responds to its ligands, by dimerizing and inducing autophosphorylation of c-terminal tyrosines. It is the phosphorylation of these tyrosines that leads to the recruitment of cellular proteins to transduce signals through the cell, promoting biological processes such as cell growth and survival. In addition to this “autophosphorylation” of the EGFR, tyrosines on the EGFR can be phosphorylated by other kinases, including the non-receptor tyrosine kinase c-Src. Of interest, c-Src is overexpressed in over 70% of breast cancers and is co-overexpressed with the EGFR in about 30% of breast cancers. These 30% of breast cancers that overexpress both tyrosine kinases tend to correlate with advanced disease, such that patients have invasion of the tumor into the basement membrane, local and distant metastasis, and/or a shorter time to progression. These observations suggest that EGFR and c-Src may be collaborating to promote tumor progression. In that regard, tissue culture models have demonstrated that EGFR/c-Src co-overexpression in murine fibroblasts leads to synergistic increases in DNA synthesis, anchorage independent cell growth, and tumor growth in nude mice. Our laboratory has three main projects focused on the co-expression of EGFR and c-Src in breast cancer.
First, one of our objectives is to improve the treatment of triple negative breast cancer patients with EGFR expression. Currently these patients have the poorest survival rates and the highest rates of recurrence. Molecular targets, such as EGFR, for triple negative breast cancers have been identified but treatment regimens abrogating the activity of the EGFR have been ineffective. Therefore, our laboratory is working on determining how to exploit the EGFR overexpression in triple negative breast cancers for therapeutic intervention. We have identified c-Src and c-Met as two tyrosine kinases that have the ability to transphosphorylate the EGFR in breast cancer cells. In addition, inhibiting c-Src or c-Met kinase activity overcomes resistance to EGFR kinase inhibitors in these breast cancer cells. However, c-Src and c-Met are not contributing to EGFR transphosphorylation and growth in all of the breast cancer cell lines we study and therefore our current research goal is to identify additional tyrosine kinases important in transphosphorylation of the EGFR, in a sense identifying the EGFR kinome.
Second, we are studying the significance of EGFR and c-Src co-localization to membrane microdomains in breast cancer. We have found that EGFR and c-Src co-localize to membrane microdomains and have the ability to mediate ligand-independent activation of EGFR signaling pathways. Specifically, we have found that in the absence of ligand, membrane microdomains are required for the phosphorylation of Akt in the SUM159 breast cancer cell line. Our objective on this project is to determine if inhibiting the formation of membrane microdomains with cholesterol inhibitors will improve the ability of breast cancer patients to respond to EGFR treatment.
Our third project in the laboratory is to determine the role of EGFR and c-Src in migration, invasion, and metastasis. To date, we have found that breast cancer cells expressing high levels of EGFR and c-Src exhibit elevated levels of EGF-dependent migration. This migration is dependent on the kinase activity and expression of EGFR and the expression of c-Src, but not the kinase activity of c-Src. Our objective is to identify the signaling mechanisms involved in this process of EGFR and c-Src mediated migration, invasion, and metastasis in breast cancer cells.
Lab members:
Kelly Mueller, Research assistant 313-576-8350 (griffink@karmanos.org)
Mary Irwin, Graduate student 313-576-8350 (irwinm@karmanos.org)
Recent publications:
Boerner, JL, Demory, ML, Silva, CM and Parsons, SJ. (2004) Phosphorylation of Y845 on the EGFR mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Molecular and Cellular Biology 24:7059-7071.
Boerner, JL, Gibson, MA, Posner, ED, Laughlin, KK, Parsons, SJ, Silva, CM, and Shupnik, MA. (2005) Estrogen negatively regulates EGF-mediated STAT5 signaling in HER family receptor overexpressing breast cancer cells. Molecular Endocrinology 19:2660-2670.
Boerner, JL, Biscardi, J, Silva, CM and Parsons, SJ. (2005) Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis. Molecular Carcinogenesis 44:262-273.
Streicher, KL, Willarth, NE, Garcia, J, Boerner, JL, Dewey, TG, Ethier, SP (2007) Activation of an NF-kB/IL-1 positive feedback loop by amphiregulin in human breast cancer cells. Molecular Cancer Research 5:847-861.
Mueller, KL, Hunter, LM, Ethier, SP, Boerner, JL (2008) Met and c-Src cooperate for loss of EGFR kinase activity in breast cancer cells. Cancer Research 68(9): 3314-3322.
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