MALIGNANT BREAST EPITHELIUM SELECTS FOR INSULIN-LIKE GROWTH-FACTOR-IIEXPRESSION IN BREAST STROMA - EVIDENCE FOR PARACRINE FUNCTION

Paracrine interactions between stromal and epithelial cells are import ant influences on the growth and malignant behavior of breast cancers, Insulin-like growth factors I and II (IGF-I and II) are expressed by fibroblasts in benign and malignant breast lesions, and both are stron g mitogens for a number of breast cancer epithelial cell lines in vitr o, We have analyzed the stromal mRNA expression of IGF-I and IGF II in matched sets of fibroblast cell lines derived from three locations in the affected breast of eight patients with breast cancer: (a) the bre ast tumor itself; (b) surrounding normal breast tissue; and (c) overly ing breast skin. IGF-I expression was easily detected in all fibroblas ts derived from normal breast tissue. In general, lesser amounts of IG F-I mRNA were detected in fibroblasts derived from breast tumors or sk in, In contrast, IGF-II expression was detected at very low levels in only 3 of 8 normal breast fibroblasts, but was present in 6 of 8 tumor fibroblasts, IGF-II mRNA was expressed in all skin fibroblasts tested . IGF-II-negative stromal fibroblasts from normal breast, which were p lated at low density and allowed to grow to confluence in the presence of MCF-7 breast tumor epithelial cells, demonstrated a marked increas e in IGF-II mRNA expression, IGF II in situ hybridization studies conf irmed that IGF-II expression is seen at high levels in stroma of many invasive breast cancers but not normal breast. We conclude that paracr ine influences, mediated by soluble factors released by breast tumor e pithelium, are able to specifically increase expression of IGF-II in b reast stroma, most likely by a process of clonal selection.