Epidermal growth factor receptor (EGFR) is critically involved in the genesis and progression of human cancers and is considered as an attractive target for anti-cancer therapy. However, clinical success with anti-EGFR therapy remains limited in part due to our incomplete knowledge of the EGFR pathway. Accumulating evidences revealed a novel mode of EGFR signaling in which EGF ligand shuttles EGFR into the nucleus, leading to cyclin D1 gene activation. Patients with breast tumors that contain high nuclear EGFR survived poorly compared to those with no/low levels. However, the nature and pathological significance of this novel EGFR network remain largely unknown. We will test the hypothesis that nuclear EGFR functions as both a transcriptional regulator and a tyrosine kinase and that de-regulated nuclear EGFR pathway contributes to a more aggressive biology of human tumors. Preminary data indicate a novel nuclear interaction between EGFR and the oncogenic transcription factor, signal transducer and activator of transcription-3, STATS, leading to increased expression of inducible nitric oxide synthase (iNOS).
Aim 1 will characterize nuclear EGFR/STAT3 interaction and determine its role in iNOS gene regulation. Moreover, whether nuclear EGFR also functions as a tyrosine kinase remains unknown. Interestingly, preliminary results suggest that nuclear EGFR phosphorylates c-jun. In addition, we found that EGF activates expression of TWIST, a mediator for epithelial-mesenchymal transition (EMT)/metastasis and that TWIST gene promoter can be regulated by EGFR, c-jun and STATS.
Aim 2 will thus determine the effect of EGFR/ c-jun/STAT3 interplay on TWIST gene activation and TWIST-mediated EMT/tumor progression. A role of nuclear EGFR in Taxol/5-Fu resistance is suggested by our preliminary data.
Aim 3 will determine the significance and mechanisms for nuclear EGFR-mediated chemoresistance. This proposal is highly relevant to public health and its outcome will shed light into the nuclear EGFR signaling network in human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA118423-05
Application #
7892332
Study Section
Subcommittee G - Education (NCI)
Program Officer
Schmidt, Michael K
Project Start
2006-09-25
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$128,600
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Carpenter, R L; Paw, I; Dewhirst, M W et al. (2015) Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells. Oncogene 34:546-57
Carpenter, Richard L; Lo, Hui-Wen (2014) STAT3 Target Genes Relevant to Human Cancers. Cancers (Basel) 6:897-925
Zhu, Hu; Carpenter, Richard L; Han, Woody et al. (2014) The GLI1 splice variant TGLI1 promotes glioblastoma angiogenesis and growth. Cancer Lett 343:51-61
Carpenter, Richard L; Lo, Hui-Wen (2013) Regulation of Apoptosis by HER2 in Breast Cancer. J Carcinog Mutagen 2013:
Carpenter, Richard L; Han, Woody; Paw, Ivy et al. (2013) HER2 phosphorylates and destabilizes pro-apoptotic PUMA, leading to antagonized apoptosis in cancer cells. PLoS One 8:e78836
Han, Woody; Carpenter, Richard L; Cao, Xinyu et al. (2013) STAT1 gene expression is enhanced by nuclear EGFR and HER2 via cooperation with STAT3. Mol Carcinog 52:959-69
Carpenter, Richard L; Lo, Hui-Wen (2012) Hedgehog pathway and GLI1 isoforms in human cancer. Discov Med 13:105-13
Cao, X; Geradts, J; Dewhirst, M W et al. (2012) Upregulation of VEGF-A and CD24 gene expression by the tGLI1 transcription factor contributes to the aggressive behavior of breast cancer cells. Oncogene 31:104-15
Carpenter, Richard L; Lo, Hui-Wen (2012) Identification, functional characterization, and pathobiological significance of GLI1 isoforms in human cancers. Vitam Horm 88:115-40
Han, Woody; Lo, Hui-Wen (2012) Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett 318:124-34

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