Abstract

The gene encoding the receptor tyrosine kinase (RTK) HER2/neu/ErbB2 is an important human breast cancer oncogene, and a validated therapeutic target. We hypothesize that optimal development and use of ErbB2-targeted therapeutics will require a thorough understanding of the normal biological functions of ErbB2 and its regulation by interactions with other ErbB family receptors.
Aim 1 continues our analysis of normal functions of ErbB2 and ErbBS in mammary gland development.
Aim 2 investigates a new hypothesis in which excessive signaling through ErbB2 drives genomic instability in breast cancer through actuation of DNA checkpoint signaling and selection for checkpoint bypass.
Aim 3 will evaluate phosphorylation markers for measuring for ErbB and pathway activation in human cancer n the best-case setting of core biopsies. The significance of these studies extends well beyond breast cancer, since the Epidermal Growth Factor Receptor (EGFR) and ErbB2 are mutated or overexpressed in many types of adenocarcinoma. Since ErbBs are forefront targets for new RTK inhibitors in cancer treatment, success of our efforts to merge ErbB biology with tumor studies will pave the way for similar approaches to cancers caused by other RTKs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045708-23
Application #
8109922
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
1987-07-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
23
Fiscal Year
2011
Total Cost
$336,647
Indirect Cost

  Institution

Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

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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