Angiogenic growth factors in preinvasive breast disease

Recently, we showed that preinvasive breast pathologies, such as usual hyperplasia, atypical hyperplasia, and carcinoma in situ, have an increased vascularity when compared with normal breast tissue (S. C. Heffelfinger et al., Clinical Cancer Res., 2: 1873-1878, 1996). To understand the mechanism of this increased vascularity, we examined by immunohistochemistry each of these pathological lesions for the expression of angiogenic growth factors. These studies showed that normal breast tissue contains numerous angiogenic agents, particularly vascular endothelial cell growth factor and basic fibroblast growth factor. At the transition from normal epithelium to proliferative breast disease, insulin-like growth factor (IGF) II expression was increased, primarily in the stroma and infiltrating leukocytes. However, among proliferative tissues, IGF I decreased with increasing vascularity. Finally, both epithelial vascular endothelial growth factor and epithelial and leukocytic platelet-derived endothelial cell growth factor increased at the transition to carcinoma in situ, whereas stromal and leukocytic basic fibroblast growth factor were elevated only in invasive carcinoma. Therefore, during histological progression there is also a complex progression of angiogenic growth factors. For CIS, two forms of vascularity are found: stromal microvascular density (MVD), and vascularity associated with the epithelial basement membrane (vascular score). There was 35% discordance between these two measurement systems. Among carcinoma in situ cases, decreases in stromal IGF II were associated with increasing vascular scores but not MVD, and increases in platelet-derived endothelial cell growth factor were associated with increasing MVD but not the vascular score. The presence of discordance and differential association with specific angiogenic agents suggests that these two forms of vascularity may be differentially regulated.