Various investigators have shown that the IGFs are mitogens for breast cancer cells. The expression of the IGF receptors is seen in most breast cancer cell lines and tissues, suggesting that most breast cancers have the ability to respond to the IGFs. Although authentic IGF-I is not expressed by breast cancer cell lines, it is possible that an IGF-related peptide that can be detected immunologically is expressed. Furthermore, in estrogen responsive xenotransplants, changes in the level of IGF-II mRNA correlate directly with estrogen-mediated changes in tumor growth. These observations suggest that IGF-II may be important in tumorigenesis and may serve as an autocrine growth stimulator of breast cancer cells. When human breast cancer tissues are studied, IGF-I and IGF-II mRNA expression are commonly seen. However, in situ hybridization studies suggest that IGF-I mRNA is expressed mainly by the stromal elements, while IGF-II mRNA can be found both in stroma and malignant epithelial cells. These observations support the studies done with breast cancer cell lines; IGF-I may stimulate cells via a paracrine pathway, while IGF-II may act as both an autocrine and paracrine growth factor. In addition, IGF-BPs are commonly expressed by breast cancer cells in culture, and it is possible that expression of the IGF-BPs act to modulate the effects of either IGF-I or IGF-II. We propose that the IGFs are important stimulators of breast cancer cells and that their growth promoting effects may be mediated by autocrine, paracrine, or endocrine mechanisms. Furthermore, interactions between the stroma and malignant epithelial cells may be important in regulating the growth of breast cancer. The biological importance of a fibroblast-epithelial cell interaction has been demonstrated in a normal mouse mammary cell line; morphological and functional changes in epithelial cells were induced when the cells were in direct contact with fibroblasts. Similar mechanisms may be important in malignant breast epithelial cells. For example, many breast cancer cells produce platelet-derived growth factor (PDGF) yet have no PDGF receptor. PDGF has been demonstrated to increase IGF-I production by fibroblasts, and a dual paracrine pathway involving PDGF and IGF-I expression by epithelial cells and stromal cells could be envisioned. The pathways through which the IGF system may function in human breast cancer are schematically represented in figure 1. Further work in our laboratory is directed at clarifying the role for the IGFs in breast cancer growth.