The gene encoding the HER2/neu/ErbB2 receptor tyrosine kinase is one of a small number of gene known to be altered in human breast carcinoma, and is a validated therapeutic target. We hypothesize that optima development and DEPLOYMENT of such therapeutics requires a thorough understanding of the normal biological function of ErbB2, including its normal functions in the mammary gland, and its regulation by interactions with other ErbB family receptors.
Aim continues our ongoing work on basic signaling principles governing EGF family receptors Aims 2 and 3 are geared towards determining the normal function of the ErbB family receptors in normal mammary development.
Aim 1. Work in the preceding grant cycle revealed that the positioning of ErbB2 extracellular domains influence the strength or quality of the efferent signal. Comparison of transcription profiles for EGFR activated by different EGF agonists will be used to determine if this mechanism is used to generate signaling diversity among the agonists.
Aim 2. Transplantation techniques will be used to determine consequences of ErbB2 and ErbB3 gene disruption on mammary development, and whether limiting functions are performed in the stroma or epithelium.
Aim 3. Transplantation techniques will be used to determine consequences of disruption of sets of ErbB family receptors on mammary development. This work has direct relevance to breast cancer and a number of other carcinomas that overexpress HER2/neu, since the receptor is now a validated therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045708-18
Application #
6989128
Study Section
Pathology B Study Section (PTHB)
Program Officer
Perry, Mary Ellen
Project Start
1987-07-01
Project End
2007-08-06
Budget Start
2005-12-12
Budget End
2007-08-06
Support Year
18
Fiscal Year
2006
Total Cost
$346,226
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Colavito, Sierra A; Zou, Mike R; Yan, Qin et al. (2014) Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B) pathway. Breast Cancer Res 16:444
Breindel, Jerrica L; Haskins, Jonathan W; Cowell, Elizabeth P et al. (2013) EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. Cancer Res 73:5053-65
Bai, Yalai; Cheng, Huan; Bordeaux, Jennifer et al. (2013) Comparison of HER2 and phospho-HER2 expression between biopsy and resected breast cancer specimens using a quantitative assessment method. PLoS One 8:e79901
Held, Matthew A; Langdon, Casey G; Platt, James T et al. (2013) Genotype-selective combination therapies for melanoma identified by high-throughput drug screening. Cancer Discov 3:52-67
Stern, David F (2011) ""Competence"" progress. Mol Cell 42:411-2
Tworkoski, Kathryn; Singhal, Garima; Szpakowski, Sebastian et al. (2011) Phosphoproteomic screen identifies potential therapeutic targets in melanoma. Mol Cancer Res 9:801-12
Bai, Yalai; Tolles, Juliana; Cheng, Huan et al. (2011) Quantitative assessment shows loss of antigenic epitopes as a function of pre-analytic variables. Lab Invest 91:1253-61
Singhal, G; Akhter, M Z; Stern, D F et al. (2011) DNA triplex-mediated inhibition of MET leads to cell death and tumor regression in hepatoma. Cancer Gene Ther 18:520-30
Stern, David F (2010) EGFs and ERBBs--brief history and prospects. Semin Cell Dev Biol 21:917-21
Agarwal, S; Zerillo, C; Kolmakova, J et al. (2009) Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells. Br J Cancer 100:941-9

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