Expression of Angiogenic Factors Is Upregulated in DMBA-Induced Rat Mammary Pathologies

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Abstract
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 ≤ 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.