Technical Description: ErbB2 (Her2/Neu) overexpression is found in 20-30% of breast cancer patients as well as other cancers, and signifies poor prognosis. Success with humanized anti-ErbB2 antibodies has further validated ErbB2 as a therapeutic target. Ansamycin HSP90 inhibitors, such as 17AAG, are in phase l/ll clinical studies as novel anticancer agents as they target ErbB2 and other signaling proteins for ubiquitin-dependent degradation. Based on recent studies by us and others, we hypothesize that CHIP (C-terminus of HSP70-lnteracting Protein) and additional hitherto unknown ubiquitin ligases mediate 17AAG-induced ErbB2 downregulation either through proteasomal or through lysosomal degradation. Here, we propose comprehensive strategies to test these hypotheses. We will carry out cell biological, molecular and biochemical studies to distinguish whether HSP90 inhibitor-driven ErbB2 downregulation is mediated through degradation in the proteasome, lysosome or both. We will examine the role of CHIP and several candidate proteins identified through bioinformatics in 17AAG-induced ErbB2 ubiquitinylation and degradation, proliferation and survival of ErbB2 overexpressing breast cancer cell lines and in their in vivo growth in nude mice, using overexpression, dominant-negative mutant expression and RNAi knockdown strategies. If additional unknown ubiquitin ligases appear likely to mediate 17AAG-induced ErbB2 degradation, we will employ proteomics and yeast two-hybrid approaches to identify these proteins and characterize them functionally as for CHIP and other candidates. Through this comprehensive approach, we hope to elucidate the biological basis of ErbB2 downregulation by HSP90 inhibitory drugs and their anticancer activity. Success of these studies will open new therapeutic avenues for ErbB2-driven cancers as well those caused by EGFRvlll, an ErbB1 variant with biological similarities with ErbB2. Relevance to Public Health: This proposal will investigate new means of interfering with a cancer-causing protein Her2/Neu that is highly increased in 20-30% breast cancers with worst prognosis. The proposed studies could provide a basis for newer, more effective targeted therapies against breast and other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116552-04
Application #
7632179
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$279,300
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Luan, Haitao; Mohapatra, Bhopal; Bielecki, Timothy A et al. (2018) Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program. Cancer Res 78:2524-2535
Iseka, Fany M; Goetz, Benjamin T; Mushtaq, Insha et al. (2018) Role of the EHD Family of Endocytic Recycling Regulators for TCR Recycling and T Cell Function. J Immunol 200:483-499
Olou, Appolinaire A; Sarkar, Aniruddha; Bele, Aditya et al. (2017) Mammalian ECD Protein Is a Novel Negative Regulator of the PERK Arm of the Unfolded Protein Response. Mol Cell Biol 37:
Nadeau, Scott A; An, Wei; Mohapatra, Bhopal C et al. (2017) Structural Determinants of the Gain-of-Function Phenotype of Human Leukemia-associated Mutant CBL Oncogene. J Biol Chem 292:3666-3682
Cypher, Luke R; Bielecki, Timothy Alan; Adepegba, Oluwadamilola et al. (2016) CSF-1 receptor signalling is governed by pre-requisite EHD1 mediated receptor display on the macrophage cell surface. Cell Signal 28:1325-35
Bhattacharyya, Sohinee; Rainey, Mark A; Arya, Priyanka et al. (2016) Endocytic recycling protein EHD1 regulates primary cilia morphogenesis and SHH signaling during neural tube development. Sci Rep 6:20727
An, Wei; Mohapatra, Bhopal C; Zutshi, Neha et al. (2016) VAV1-Cre mediated hematopoietic deletion of CBL and CBL-B leads to JMML-like aggressive early-neonatal myeloproliferative disease. Oncotarget 7:59006-59016
William, Basem M; An, Wei; Feng, Dan et al. (2016) Fasudil, a clinically safe ROCK inhibitor, decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders. Hematology 21:218-24
Goetz, Benjamin; An, Wei; Mohapatra, Bhopal et al. (2016) A novel CBL-Bflox/flox mouse model allows tissue-selective fully conditional CBL/CBL-B double-knockout: CD4-Cre mediated CBL/CBL-B deletion occurs in both T-cells and hematopoietic stem cells. Oncotarget 7:51107-51123
Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal et al. (2016) Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition. Oncotarget 7:10522-35

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