Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer. II: Correlations with proliferation and angiogenesis

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Abstract
Growth factors may play an important role in tumour growth and angiogenesis by their influence on tumour cell proliferation or their effect on neovascularization. The aim of the present study was to determine which of the growth factors, growth‐inhibiting factors, and their receptors investigated in a previous study are correlated with proliferation and angiogenesis in invasive breast cancer, with emphasis on the impact of possible autocrine and paracrine loops. Five growth factors and their receptors: platelet‐derived growth factor A chain (PDGF‐AA) and PDGF alpha receptor (PDGFαR), PDGF‐BB and PDGF beta receptor (PDGFβR), transforming growth factor alpha (TGFα) and its receptor epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) and its receptors (Flt‐1 and Flk‐1/KDR; two growth‐inhibiting factors: transforming growth factor beta‐1 (TGFβ1) and TGFβ2 and their receptor couple TGFβR‐I and TGFβR‐II; and basic fibroblast growth factor (bFGF) were stained in 45 cases of invasive breast cancer by standard immunohistochemistry on frozen sections. Staining in tumour cells, stromal cells, and endothelial cells was scored as negative or positive. Proliferation was determined by assessment of the mitotic activity index (MAI) and the degree of angiogenesis was measure by counting the number of microvessels (microvessel density: MVD) in the most vascularized area of the tumour. bFGF and EGFR showed positive correlations with the MAI, while TGFβ2 showed a negative correlation. Expression of bFGF, TGFα, TGFβ2, and EGFR correlated positively with the MVD. Co‐expression of the TGFα/EGFR growth factor/receptor combination showed a stronger correlation with the MAI and the MVD than EGFR or TGFα alone, and the TGFβ2/TGFβR‐I/TGFβR‐II combination showed a positive correlation with the MVD. In conclusion, the expression of several growth factors, growth factor receptors, and growth‐inhibiting factors showed correlations with the rate of proliferation and the degree of angiogenesis in invasive breast cancer. Some growth factor/receptor combinations showed stronger correlations with proliferation and angiogenesis than the growth factor or receptor alone, pointing to the importance of possible auto‐ and paracrine loops for stimulation of proliferation and angiogenesis by growth factors and their receptors. © 1998 John Wiley & Sons, Ltd.