Growth factors of the Epidermal Growth Factor family play pivotal roles in development of the nervous system and the cardiovascular system. Interest in the functions of these hormones and receptors in the mammary gland is driven by the importance of the Epidermal Growth Factor Receptor and the related receptor ErbB2 in breast cancer and in other carcinomas. Both receptors are under intensive investigation as therapeutic targets in cancer, and the latter is the validated therapeutic target for the FDA-approved drug Trastuzumab/Herceptin. In contrast to Epidermal Growth Factor Receptor and ErbB2, the related receptor ErbB4 seems to be linked to terminal differentiation of the mammary gland, and may antagonize carcinogenesis. We will determine whether ErbB4 is important as a negative or positive regulator in human breast cancer and in a mouse model for ErbB2-mediated carcinogenesis, and will determine what the normal functions are for ErbB4 in the mammary gland.
Aim 1 will determine the associations of ErbB4 expression with clinical outcome in a large panel of human breast carcinoma specimens with long-term followup data. The effect of gene disruption of ErbB4 on the timing of MMTV-Neu induced carcinoma in transgenic mice will be determined.
Aim 2 will determine the mammary phenotypes associated with disruption of ErbB4 in mouse.
Aim 3 will investigate signal transduction mechanisms linked to processes that are found to be important in Aim 2. The results will indicate whether ErbB4 expression has prognostic significance, and will suggest whether modulation of ErbB4-activated pathways will be beneficial to cancer patients. Since ErbB4 is also important in developing an adult nervous system, neuromuscular junction, and heart, information about the mechanisms of ErbB4 signal transduction may help develop treatments for nerve and muscle damage disorders, and cardiovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080065-07
Application #
6919940
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Perry, Mary Ellen
Project Start
1998-12-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
7
Fiscal Year
2005
Total Cost
$376,474
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Haskins, Jonathan W; Zhang, Shannon; Means, Robert E et al. (2015) Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake. Sci Signal 8:ra111
Haskins, Jonathan W; Nguyen, Don X; Stern, David F (2014) Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration. Sci Signal 7:ra116
Wali, Vikram B; Gilmore-Hebert, Maureen; Mamillapalli, Ramanaiah et al. (2014) Overexpression of ERBB4 JM-a CYT-1 and CYT-2 isoforms in transgenic mice reveals isoform-specific roles in mammary gland development and carcinogenesis. Breast Cancer Res 16:501
Wali, Vikram B; Haskins, Jonathan W; Gilmore-Hebert, Maureen et al. (2014) Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells. Mol Cancer Res 12:1140-55
Hatzis, Christos; Bedard, Philippe L; Birkbak, Nicolai J et al. (2014) Enhancing reproducibility in cancer drug screening: how do we move forward? Cancer Res 74:4016-23
Gilmore-Hebert, Maureen; Ramabhadran, Rajani; Stern, David F (2010) Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Mol Cancer Res 8:1388-98
Jackson-Fisher, A J; Bellinger, G; Shum, E et al. (2006) Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4. Oncogene 25:5664-72
Amin, Dhara N; Tuck, David; Stern, David F (2005) Neuregulin-regulated gene expression in mammary carcinoma cells. Exp Cell Res 309:12-23
Amin, Dhara N; Perkins, Archibald S; Stern, David F (2004) Gene expression profiling of ErbB receptor and ligand-dependent transcription. Oncogene 23:1428-38
Tidcombe, Hester; Jackson-Fisher, Amy; Mathers, Kathleen et al. (2003) Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A 100:8281-6

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