Expression of angiogenic factors is upregulated in DMBA-induced rat mammary pathologies.
OBJECTIVE
In the 7,12-dimethylbenz[a]anthracene (DMBA) model of rat mammary carcinogenesis, microvascular density and angiogenic potential increase with progression from normal to invasive disease, but the mechanisms involved are unknown. Using RT-PCR, we determined the expression of angiogenic regulators in DMBA-induced intraductal hyperplasia (IDP), carcinoma in situ (CIS), invasive tumors (INV), as well as normal tissue.


METHODS
RT-PCR was performed on frozen tissue sections of each type of pathology for factors known to regulate angiogenesis in other systems.


RESULTS
MMP-2, MMP-9, uPA, PAI-1, IGF-2, BFGF, VEGF, ANG-1, IRS-1, and TSP-1 were significantly (p < or =0.05) upregulated in CIS and INV, whereas TIMP-1, ANG-2, MASPIN, IGF1-R and HBEGF were unchanged. IGF-1 was uniquely elevated in IDP. SPARC was downregulated in CIS. Inhibition of IGF-1R by the tyrphostin, AG1024, blocked endothelial tubulogenesis in vitro, confirming that IGF-1 functions as a regulator of angiogenesis.


CONCLUSIONS
These data support the involvement of specific angiogenic mediators in mammary tumor formation. Angiogenesis at different stages of tumorigenesis may be regulated by unique factors.
Department of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio 45367-0529, USA.
Mei
M
Yan
Joanne
J
Schneider
Robin
R
Gear
Fengxian
F
Lu
Kathy
K
LaDow
David
D
Warshawsky
Sue C
SC
Heffelfinger
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D042501:Angiogenic Proteins / Q000096:biosynthesis* / Q000235:genetics; D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002278:Carcinoma in Situ / Q000139:chemically induced* / Q000235:genetics; D044584:Carcinoma, Ductal / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006965:Hyperplasia; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D015676:Osteonectin / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D042501:Angiogenic Proteins; D042683:Angiopoietin-1; D002273:Carcinogens; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D015676:Osteonectin; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D015127:9,10-Dimethyl-1,2-benzanthracene; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9