Estrogens and insulin-like growth factors (IGFs) act as mitogens promoting cell proliferation in normal breast tissue as well as in breast carcinomas. Both hormones have been shown to play a role in the development of breast cancer and were found to activate multiple signaling pathways leading to proliferation of human breast cancer cell lines in vitro. Originally, it was considered that these agents manifest their mitogenic actions through separate pathways, but a growing body of evidence suggests that the IGF- and estrogen-mediated signaling pathways are intertwined. 17beta-Estradiol (E2) has been shown to enhance IGF signaling at multiple levels. E2 treatment of breast cancer cells alters expression of nearly all of the IGF family members including IGF-I, IGF-II, IGF-binding proteins, IGF type I receptor (IGF-RI), and insulin receptor substrate 1. The ligand-bound estrogen receptor has been reported to bind to and to activate the IGF-RI directly. Vice versa, IGF signaling has been reported to enhance estrogen receptor activation in human breast cancer cells by inducing phosphorylation of the estrogen receptor. Finally, several groups have described synergistic effects of the combination of E2 and IGF-I on S phase entry in breast tumor cell lines. Here, we review recent, often contradictory, reports describing the effects of E2 and IGFs on the proliferation of breast tumor cells, with special emphasis on the synergistic effects of the two hormones.

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