EXPRESSION OF THE ANGIOGENIC FACTORS VASCULAR ENDOTHELIAL-CELL GROWTH-FACTOR, ACIDIC AND BASIC FIBROBLAST GROWTH-FACTOR, TUMOR-GROWTH FACTOR-BETA-1, PLATELET-DERIVED ENDOTHELIAL-CELL GROWTH-FACTOR, PLACENTA GROWTH-FACTOR, AND PLEIOTROPHIN IN HUMAN PRIMARY BREAST-CANCER AND ITS RELATION TO ANGIOGENESIS

Angiogenesis is a significant prognostic factor in breast cancer, but the factors that control angiogenesis irt vivo are not well defined, M ultiple angiogenic polypeptides are known, and we have determined the expression of seven of these in primary human breast cancers; the rela tionship of expression to estrogen receptor and vascular density was a lso examined, Vascular endothelial growth factor (VEGF) and its four i soforms (121, 165, 189, and 206 amino acids), transforming growth fact or (TGF)-beta 1, pleiotrophin, acidic and basic fibroblast growth fact or (FGF), placental growth factor, and thymidine phosphorylase (platel et-derived endothelial cell growth factor) were quantitated by RNase p rotection analysis, beta-FGF was also measured by ELISA. The estrogen receptor (ER), epidermal growth factor receptor, and vascular density mere analyzed in 64 primary breast cancers, All tumors expressed at le ast six different vascular growth factors, VEGF was most abundant, and the transcript for the 121-amino acid form predominated, Other angiog enic factors expressed at high levels were thymidine phosphorylase and TGF-beta 1. Expression of most of the angiogenic factors did not corr elate with that of ER or vascular density, However, thymidine phosphor ylase did, with a correlation coefficient of 0.3 (P = 0.03), There wer e significant associations of pleiotrophin with acidic FGF expression (P = 0.001) and TGF-beta with platelet-derived endothelial cell growth factor expression (P = 0.001), Thus, angiogenesis may involve a coord inate regulation of some vascular growth factors, High VEGF expression correlated with poor prognosis in univariate analysis (P = 0.03), as did ER and epidermal growth factor receptor expression, Basic FGF was also assessed by ELISA and was more highly expressed in tumors than no rmal breast tissues (median, 346 mu g/ml cytosol; range, 54-1323 versu s median, 149; range, 32-509; P = 0.01), Implications for therapy are that broad spectrum agents that block features common to these factors may be useful (e.g., antagonism of heparin-binding activity agents), because so many angiogenic factors are expressed, Inhibiting endotheli al migration or agents directly toxic to endothelium would be of value in a combined approach to therapy.