Role of estrogen-induced insulin-like growth factors in the proliferation of human breast cancer cells.

Insulin-like growth factor I (IGF-I) is the most potent growth factor for estrogen (E2)-dependent breast cancer cell lines. It has been reported that such cell lines produce an immunoreactive IGF-I-related protein in an E2-dependent fashion, while autonomously growing cell lines constitutively produce these factors, indicating that they might be involved in autocrine growth stimulation of breast cancer cells. We have studied the role of IGFs in autocrine growth stimulation of the E2-dependent breast cancer cell line MCF7 by using IGF-binding proteins (BPs) that were able to neutralize completely the mitogenic effect of IGF-I on this cell line. These BPs, however, did not have any inhibitory effect on E2-induced mitogenesis, suggesting that secretion of autocrine IGFs is not involved in growth stimulation by E2. To exclude the possibility that variants of IGF are produced by the cells that are not recognized by the BPs, we also studied the production of biologically active IGF using the same MCF7 cell line in a sensitive bioassay in which the various forms of IGF and insulin can be detected. Although the conditioned medium (CM) of human fibroblasts used as a control showed IGF-like activity in this assay, no such activity was detected in CM of both untreated and E2-stimulated MCF7 cells, while the CM of the E2-independent cell lines BT20 and Hs578T had only slight mitogenic activity or was even growth inhibitory, respectively. These data show that no significant secretion of biologically active IGFs by human breast cancer cells could be detected and do not support a possible autocrine function of IGFs in the proliferation of such cells. Because E2-dependent cells strongly react to externally added IGF-like factors produced by human fibroblasts, a role for IGFs in paracrine regulation of proliferation is suggested.