Breast cancer can be treated and prevented by interrupting the function of key growth regulatory receptors. There is a large body of evidence showing that the insulin-like growth factors (IGFs) stimulate several phenotypes characteristic of the malignant breast cancer cell including proliferation, protection from apoptosis, and metastasis. IGF action is potentially mediated by several distinct cell surface receptors. Unlike some growth factor receptors implicated in breast cancer biology, the IGF receptors require interaction with their ligands in order to transmit a relevant biological signal. Thus, the goal of this project is to neutralize IGF action as a method to inhibit breast cancer growth. We hypothesize that inhibition of IGF action by insulin-like growth factor binding protein-1 (IGFBP-1) will be an effective anti-tumor strategy and synergize with other anti-breast cancer strategies. We also will examine if the integrin binding sequence (RGD) contained in IGFBP-1 contributes to its anti-tumor effects.
Our specific aims are to: 1) manipulate the pharmacologic properties of IGFBP-1 to maximize its therapeutic effect; 2) use IGFBP-1 to inhibit breast cancer growth in xenograft and transgenic mouse models of breast cancer; 3) combine IGFBP-1 with cytotoxic chemotherapy to enhance breast cancer tumor inhibition; and 4) determine if the integrin binding protein (RGD) motif contained in IGFBP-1 is required for its anti-tumor effects. Our long-term goal is to prove that the IGFs are key targets for the treatment of breast cancer. By optimizing IGF neutralization strategies, we will be prepared to move this anti-IGF strategy into the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA089652-01A1
Application #
6431039
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$264,330
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Organized Research Units
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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; Yee, Douglas (2007) Insulin-like growth factors and breast cancer therapy. Adv Exp Med Biol 608:101-12
Yee, D (2006) Targeting insulin-like growth factor pathways. Br J Cancer 94:465-8
Ramakrishnan, S; Subramanian, I V; Yokoyama, Y et al. (2005) Angiogenesis in normal and neoplastic ovaries. Angiogenesis 8:169-82
Ibrahim, Yasir H; Yee, Douglas (2004) Insulin-like growth factor-I and cancer risk. Growth Horm IGF Res 14:261-9
Yokoyama, Yumi; Ramakrishnan, S (2004) Addition of integrin binding sequence to a mutant human endostatin improves inhibition of tumor growth. Int J Cancer 111:839-48