The ERBB/EGFR family member HER4/ERBB4 has critical functions during normal development and influences the progression of human cancer. Proteolytic processing of ERBB4 at the cell surface releases an independently signaling ERBB4 intracellular domain (4ICD) with multiple divergent cellular activities. On the one hand 4ICD translocates to the nucleus in response to estrogen and coactivates gene expression by selectively binding with estrogen receptor to a subset of estrogen response gene promoters. On the other hand an ERBB4 ligand, HRG, promotes 4ICD translocation to mitochondria where 4ICD induces tumor cell apoptosis by functioning as a novel BH3-only protein (proapoptotic members of the BCL-2 family). Despite experimental descriptions of novel 4ICD activities, this unique signaling paradigm remains to be substantiated in physiologically relevant biological systems. Nuclear 4ICD within mammary epithelium coincident with the essential contributions of ERBB4 to lactation supports the hypothesis that 4ICD contributes to mammopoesis. We also hypothesize that novel 4ICD signaling events regulate estrogen activity in breast tumor cells and mediate the response of breast cancer patients to endocrine therapy. We propose to test these related hypotheses by pursuing the following specific aims: Using mice with mutant ERBB4 alleles that abolish proteolytic processing we propose to (Aim 1) identify the contribution of ERBB4 processing and 4ICD nuclear localization to mammary gland development. We propose to employ global gene expression and promoter binding assays to (Aim 2) identify the molecular basis of coupled 4ICD/ER? signaling contributing to breast tumor cell proliferation. Clinical studies suggest that women with tumors coexpressing ER? and ERBB4 fare better when treated with endocrine therapy then women lacking tumor ERBB4 expression. Our data demonstrates that the 4ICD BH3-only protein is a key regulator of tamoxifen response and extinguished breast tumor cell expression of 4ICD results in tamoxifen resistance. We propose to (Aim 3) test the hypothesis that tumor expression of ERBB4/4ICD can be used a marker to predict clinical response to tamoxifen. We predict that our results will represent the first physiologically relevant contribution to the emerging field of cell-surface receptor signaling to the nucleus and have a major impact on therapeutic decisions affecting over 70% of breast cancer patients.

Public Health Relevance

Results from the proposed experiments will stimulate an intellectual and experimental paradigm shift with an emphasis on ERBB4/4ICD as a critical regulator of tamoxifen response in breast cancer patients. Thus we predict that our results will impact the majority of breast cancer patients and lay the foundation for the development of ERBB4/4ICD as an important tumor marker predicting clinical response to tamoxifen. By extension ERBB4/4ICD expression will be used to guide therapeutic decisions with patients with ERBB4/ER(+) tumors benefiting from tamoxifen whereas patients with ERBB4(-)/ER(+) tumors would be better served with a clinical regimen where tamoxifen was augmented or supplanted by another therapeutic approach.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA095783-10
Application #
8063829
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2001-09-21
Project End
2014-04-30
Budget Start
2010-08-16
Budget End
2011-04-30
Support Year
10
Fiscal Year
2010
Total Cost
$264,129
Indirect Cost
Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
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

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