Constitutive signaling by the Epidermal Growth Factor (EGF) Receptor (EGFR/c-ErbB1) frequently leads to increased tumor cell proliferation, motility, invasiveness and metastasis. Molecules that inhibit EGFR expression or activity are being assessed as potential antineoplastic agents.
One specific aim of this study is to identify which set of putative EGFR tyrosine kinase inhibitors has the highest specific activity.
A second aim i s to assess the effects of this EGFR kinase inhibitor(s) on the proliferation, motility and invasiveness of a panel of human mammary tumor cell lines. Such experiments will enable us to evaluate whether this compound(s) merits additional study as a potential treatment. EGFR is a member of the ErbB family of receptor tyrosine kinases, a family that includes three other members: Neu/ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. Ligands for these receptors are members of the EGF family of peptide hormones. Overexpression of at least two EGF family hormones, amphiregulin (AR) and transforming growth factor alpha (TGFalpha ), induces tumor cell proliferation, motility, invasiveness, and metastasis. Another EGF family hormone, Neuregulin-1 (NRG1), induces tumor cell differentiation and growth arrest. However, NRG1 activates a different set of ErbB family receptors than do AR and TGFalpha . Through collaborations, we have acquired cDNAs for three novel family hormones: NRG2, NRG3, and NRG4. Our third specific aim is to generate recombinant forms of these proteins. The fourth specific aim of this study is to identify which ErbB family receptors are activated by these hormones, using both human breast tumor cell lines and cell lines expressing defined combinations of receptors. Our fifth specific aim is to assess the effects of these hormones on breast tumor cell line proliferation, motility, and invasiveness. Finally, we will attempt to correlate the biological response of a given cell line to a given EGF family hormone to which ErbB family receptors are activated by that hormone in that cell line.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Pathology B Study Section (PTHB)
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Ault, Grace S
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Purdue University
Schools of Pharmacy
West Lafayette
United States
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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
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
Wilson, Kristy J; Gilmore, Jennifer L; Foley, John et al. (2009) Functional selectivity of EGF family peptide growth factors: implications for cancer. Pharmacol Ther 122:1-8
Wilson, Kristy J; Mill, Christopher P; Cameron, Elizabeth M et al. (2007) Inter-conversion of neuregulin2 full and partial agonists for ErbB4. Biochem Biophys Res Commun 364:351-7
Pitfield, Sarah E; Bryant, Ianthe; Penington, Desi J et al. (2006) Phosphorylation of ErbB4 on tyrosine 1056 is critical for ErbB4 coupling to inhibition of colony formation by human mammary cell lines. Oncol Res 16:179-93
Gilmore, Jennifer L; Gallo, Richard M; Riese 2nd, David J (2006) The epidermal growth factor receptor (EGFR)-S442F mutant displays increased affinity for neuregulin-2beta and agonist-independent coupling with downstream signalling events. Biochem J 396:79-88
Gallo, Richard M; Bryant, Ianthe; Fry, Rachael et al. (2006) Phosphorylation of ErbB4 on Tyr1056 is critical for inhibition of colony formation by prostate tumor cell lines. Biochem Biophys Res Commun 349:372-82
VanBrocklin, Henry F; Lim, John K; Coffing, Stephanie L et al. (2005) Anilinodialkoxyquinazolines: screening epidermal growth factor receptor tyrosine kinase inhibitors for potential tumor imaging probes. J Med Chem 48:7445-56
Hobbs, Stuart S; Gallo, Richard M; Riese Jr, David J (2005) Phe45 of NRG2beta is critical for the affinity of NRG2beta for ErbB4 and for potent stimulation of ErbB4 signaling by NRG2beta*. Growth Factors 23:273-83
Hobbs, Stuart S; Cameron, Elizabeth M; Hammer, Robert P et al. (2004) Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase. Oncogene 23:883-93

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