Transforming growth factor alpha (TGF-alpha), amphiregulin (AR), heparin-binding growth factor (HB-EGF), heregulin (HRG) and cripto-1 (CR-1) are proteins that are structurally and in some cases functionally related to epidermal growth factor (EGF) in that TGF- alpha, HB-EGF and AR can bind to the EGF receptor (c-erb B) whereas HRG binds to c-erbB-3 or c-erb B-4. The present studies have demonstrated that MCF-10A human mammary epithelial cells are mitogenically responsive to exogenous EGF, HB-EGF, TGF-alpha or AR and that transformation of these cells with a point-mutated c-Ha-ras protooncogene results in an increase in the expression of endogenous HB-EGF, TGF-alpha, AR and HRG whereas erb B-2 transformation of these cells results in an upregulation in only AR and HRG expression. Furthermore, overexpression of a human TGF-alpha cDNA in these cells leads to their in vitro transformation. Addition of an anti-EGF receptor blocking antibody inhibits the growth of MCF-10A transformed mammary cells suggesting that an external autocrine loop is operative in these cells. Estrogens can increase the expression of TGF-alpha and AR mRNA and protein in estrogen-responsive human breast cancer cell lines. A recombinant CR-1 protein is able to moderately stimulate the proliferation of mouse and human mammary epithelial cells and to inhibit beta-casein and whey acidic protein expression. In addition, CR-1 can stimulate branching morphogenesis of mouse mammary epithelial cells in vitro and in vivo.We have recently found that CR-1 can also induce apoptosis in a subpopulation of mammary epithelial cells through a caspase-3-dependent pathway. Finally, CR-1 can stimulate chemotaxsis and the invasion of mouse mammary epithelial cells through matrigel or type-1 collagen-coated filters. CR-1 does not directly bind to the EGF receptor nor does it directly activate the c-erb B-2, c-erb B-3 or c- erb B-4 type 1 receptor tyrosine kinases either singularly or in various heterodimeric pairwise combinations. However, CR-1 can rapidly and transiently enhance the tyrosine phosphorylation of p46 Shc and can activate the MAPK isoform, p42erk2. 125125I-CR-1 can be specifically cross-linked to a 130 kDa and a 60 kDa protein that are distinct from other erb B-related tyrosine kinases. Although CR-1 fails to directly bind to any of the four known erb tyrosine kinase receptors, it can specifically enhance the indirect tyrosine phosphorylation of erb B-4. Abrogation of erb B-4 expression or activity significantly impairs the ability of CR-1 to activate MAPK. mRNA expression for AR and CR-1 have been detected in approximately 50% to 80% of primary and metastatic human colorectal tumors, whereas only 5% of normal adjacent colon or liver tissue express these genes. Likewise,AR and CR-1 were detected in approximately 80% of primary human breast tumors at a level that exceeded the level found in adjacent normal normal mammary epithelium. - breast cancer, Cripto, EGF, growth factors, TGF,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009003-17
Application #
6289225
Study Section
Special Emphasis Panel (LTIB)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Normanno, Nicola; De Luca, Antonella; Bianco, Caterina et al. (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2-16
Bianco, Caterina; Strizzi, Luigi; Mancino, Mario et al. (2006) Identification of cripto-1 as a novel serologic marker for breast and colon cancer. Clin Cancer Res 12:5158-64
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Sun, Youping; Lowther, William; Kato, Katsuaki et al. (2005) Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling. Oncogene 24:5365-74
Bianco, Caterina; Strizzi, Luigi; Normanno, Nicola et al. (2005) Cripto-1: an oncofetal gene with many faces. Curr Top Dev Biol 67:85-133
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Bianco, Caterina; Strizzi, Luigi; Ebert, Andreas et al. (2005) Role of human cripto-1 in tumor angiogenesis. J Natl Cancer Inst 97:132-41

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