Our objective is to characterize the effects of ligand-induced ErbB4 signaling on the behavior of human breast, prostate, and pancreatic tumor cell lines. We have four specific aims: (1) Establish tumor cell model systems and determine the effects of ligand-induced ErbB4 signaling. (2) Determine the mechanisms by which ErbB4 is coupled to downstream biological effects. (3) Assess the role of ErbB receptor heterodimerization in coupling ErbB4 ligands to downstream biological effects. (4) Determine the structure of the ErbB4 extracellular domain bound to various NRG isoforms and mutants. A hypothesis that will be emphasized throughout this effort is that different Neuregulin isoforms differentially stimulate ErbB4 signaling and coupling to biological responses. The results of these experiments will shed new insight into the pathogenesis of breast, prostate, and pancreatic cancers. Moreover, they will suggest potential strategies for the treatment of these diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Woodhouse, Elizabeth
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Purdue University
Schools of Pharmacy
West Lafayette
United States
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Riese 2nd, David J; Cullum, Richard L (2014) Epiregulin: roles in normal physiology and cancer. Semin Cell Dev Biol 28:49-56
Gallo, Richard M; Bryant, Ianthe N; Mill, Christopher P et al. (2013) Multiple Functional Motifs Are Required for the Tumor Suppressor Activity of a Constitutively-Active ErbB4 Mutant. J Cancer Res Ther Oncol 1:10
Nickerson, Nicole K; Mill, Christopher P; Wu, Hsin-Jung et al. (2013) Autocrine-derived epidermal growth factor receptor ligands contribute to recruitment of tumor-associated macrophage and growth of basal breast cancer cells in vivo. Oncol Res 20:303-17
Wilson, Kristy J; Mill, Christopher P; Gallo, Richard M et al. (2012) The Q43L mutant of neuregulin 2? is a pan-ErbB receptor antagonist. Biochem J 443:133-44
Foley, John; Nickerson, Nicole; Riese 2nd, David J et al. (2012) At the crossroads: EGFR and PTHrP signaling in cancer-mediated diseases of bone. Odontology 100:109-29
Wilson, Kristy J; Mill, Christopher; Lambert, Sydney et al. (2012) EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors 30:107-16
Riese 2nd, David J (2011) Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery? Expert Opin Drug Discov 6:185-193
Zordan, Michael D; Mill, Christopher P; Riese 2nd, David J et al. (2011) A high throughput, interactive imaging, bright-field wound healing assay. Cytometry A 79:227-32
Mill, Christopher P; Gettinger, Kathleen L; Riese 2nd, David J (2011) Ligand stimulation of ErbB4 and a constitutively-active ErbB4 mutant result in different biological responses in human pancreatic tumor cell lines. Exp Cell Res 317:392-404
Foley, John; Nickerson, Nicole K; Nam, Seungyoon et al. (2010) EGFR signaling in breast cancer: bad to the bone. Semin Cell Dev Biol 21:951-60

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