Expression of three members of the ErbB-family of receptor tyrosine kinases, namely EGFR, ErbB2, and ErbB3 are associated with aggressive metastatic breast cancer. In contrast, to the mitogenic activities associated with the other three ErbB-family members, ErbB4 mediates breast epithelial differentiation and ErbB4 expression is selectively extinguished in advanced breast cancer. Furthermore, ErbB4-signaling has antiproliferative activity in breast cancer and actively curtails mitogenic signaling by the protooncogene and therapeutic target, ErbB2. Collectively, these observations support the hypothesis that ErbB4-induced differentiation pathways in breast cancer antagonize the activities of important breast oncogenes, including ErbB2. The following specific aims were designed to test this hypothesis.
Aim 1) investigate the influence of constitutive active ErbB4 (ErbB4-CA) on differentiation and ErbB2-induced cellular proliferation in human breast cancer cell lines, Aim 2) develop a preclinical transgenic mouse model of ErbB4-CA overexpression and determine the impact of ErbB4-CA on normal breast development and ErbB2-induced metastatic breast cancer, Aim 3) develop an independent preclinical mouse model to investigate the influence of extinguished ErbB4-signaling on spontaneous and ErbB2-induced breast carcinogenesis and metastasis, Aim 4) support preclinical models by determining the association of ErbB4 expression with clinical outcome and oncogenic phospho-ErbB2 expression in human primary breast tumors. The experiments described in this proposal are designed to provide a thorough analysis of ErbB4 function in the developing breast and determine the influence of ErbB4 signaling on ErbB2-induced metastatic breast cancer. If evidence suggests that ErbB4 activity antagonizes the development and progression of metastatic breast cancer in these preclinical and clinical models, future experiments will be designed to investigate the role of ErbB4 as a putative tumor suppressor in breast cancer and by extension explore the efficacy of ErbB4 signaling pathways as therapeutic agents in breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096717-04
Application #
7115706
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Snyderwine, Elizabeth G
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2006-08-11
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$320,203
Indirect Cost
Name
Tulane University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Han, Wen; Sfondouris, Mary E; Jones, Frank E (2016) Direct coupling of the HER4 intracellular domain (4ICD) and STAT5A signaling is required to induce mammary epithelial cell differentiation. Biochem Biophys Rep 7:323-327
Han, Wen; Jones, Frank E (2014) HER4 selectively coregulates estrogen stimulated genes associated with breast tumor cell proliferation. Biochem Biophys Res Commun 443:458-63
Das, P M; Thor, A D; Edgerton, S M et al. (2010) Reactivation of epigenetically silenced HER4/ERBB4 results in apoptosis of breast tumor cells. Oncogene 29:5214-9
Rokicki, Jerzy; Das, Partha M; Giltnane, Jennifer M et al. (2010) The ERalpha coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium. Mol Cancer 9:150
Thor, Ann D; Edgerton, Susan M; Jones, Frank E (2009) Subcellular localization of the HER4 intracellular domain, 4ICD, identifies distinct prognostic outcomes for breast cancer patients. Am J Pathol 175:1802-9
Naresh, Anjali; Thor, Ann D; Edgerton, Susan M et al. (2008) The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis. Cancer Res 68:6387-95
Kirkegaard, Tove; Naresh, Anjali; Sabine, Vicky S et al. (2008) Expression of tumor necrosis factor alpha converting enzyme in endocrine cancers. Am J Clin Pathol 129:735-43
Jones, Frank E (2008) HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer. J Mammary Gland Biol Neoplasia 13:247-58
Vidal, G A; Clark, D E; Marrero, L et al. (2007) A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities. Oncogene 26:462-6
Zhu, Yun; Sullivan, Lacey L; Nair, Sujit S et al. (2006) Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. Cancer Res 66:7991-8

Showing the most recent 10 out of 14 publications