In breast cancer, specific aspects of the malignant phenotype can be maintained by the interaction of growth factors with their receptors. During the last funding period, we have shown that the insulin-like growth factors (IGFs) stimulate breast cancer cell proliferation, motility, adhesion, and survival. Distinct signaling pathways have been identified that correlate with specific phenotypes. In addition, interruption of the type I IGF receptor (IGF1R) inhibits IGF action in breast cancer cells. We hypothesize that activation of IGF1R regulates specific signal transduction pathways that result in several aspect of the malignant phenotype. These findings have two important implications for breast cancer. First, by understanding the key signaling pathways regulated by IGF1R, we can better target the molecules required for the malignant behavior of breast cancer cells. Second, anti-IGF strategies need to be developed to test their therapeutic potential in the treatment of breast cancer. In this application, we propose three specific aims: 1) to determine if IRS-1 and its downstream signaling pathways are required for IGF-stimulated proliferation in breast cancer cells; 2) to determine if IRS-2 and its downstream signaling pathways are required for breast cancer cell adhesion and migration; and 3) to inhibit IGF effects in vivo with a chimeric monoclonal antibody directed against the type I IGF receptor. By performing these studies we will provide further evidence that the IGFs play a critical role in breast cancer and that targeting of the IGF1R is a feasible therapeutic strategy for treatment of this disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074285-09
Application #
6858559
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Perry, Mary Ellen
Project Start
1998-01-01
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
9
Fiscal Year
2005
Total Cost
$348,975
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Fagan, Dedra H; Fettig, Lynsey M; Avdulov, Svetlana et al. (2017) Acquired Tamoxifen Resistance in MCF-7 Breast Cancer Cells Requires Hyperactivation of eIF4F-Mediated Translation. Horm Cancer 8:219-229
Ochnik, Aleksandra M; Peterson, Mark S; Avdulov, Svetlana V et al. (2016) Amplified in Breast Cancer Regulates Transcription and Translation in Breast Cancer Cells. Neoplasia 18:100-10
Daniel, A R; Gaviglio, A L; Knutson, T P et al. (2015) Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes. Oncogene 34:506-15
Yang, Yuzhe; Yee, Douglas (2014) IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC-. Cancer Res 74:2295-305
Zhang, Xihong; Diaz, Michael R; Yee, Douglas (2013) Fulvestrant regulates epidermal growth factor (EGF) family ligands to activate EGF receptor (EGFR) signaling in breast cancer cells. Breast Cancer Res Treat 139:351-60
Zeng, Xianke; Zhang, Hua; Oh, Annabell et al. (2012) Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor. Breast Cancer Res Treat 133:117-26
Yee, Douglas (2012) Insulin-like growth factor receptor inhibitors: baby or the bathwater? J Natl Cancer Inst 104:975-81
Potter, David A; Yee, Douglas; Guo, Zhijun et al. (2012) Should diabetic women with breast cancer have their own intervention studies? Endocr Relat Cancer 19:C13-7
Fagan, Dedra H; Uselman, Ryan R; Sachdev, Deepali et al. (2012) Acquired resistance to tamoxifen is associated with loss of the type I insulin-like growth factor receptor: implications for breast cancer treatment. Cancer Res 72:3372-80
Yang, Yuzhe; Yee, Douglas (2012) Targeting insulin and insulin-like growth factor signaling in breast cancer. J Mammary Gland Biol Neoplasia 17:251-61

Showing the most recent 10 out of 47 publications