Insulin like growth factor I (IGF-I) displays estrogenic activity in breast cancer cells. This activity is strictly dependent on the presence of estrogen receptor ␣ (ER␣). However the precise molecular mechanisms involved in this process are still unclear. IGF-I treatment induces phosphorylation of the AF1 domain of ER␣ and activation of estrogen regulated genes. These genes are characterized by important differences in promoter architecture and response element composition. We show that promoter structure is crucial for IGF-I-induced transcription activation. We demonstrate that on a complex promoter such as the pS2/TFF1 promoter, which contains binding sites for ER␣ and for the activating protein-1 (AP1) complex, transcriptional activation by IGF-I requires both ER␣ and the AP1 complex. IGF-I is unable to stimulate transcription of an estrogen-regulated gene under the control of a minimal promoter containing only a binding site for ER␣. We propose a molecular mechanism with stepwise assembly of the AP1 complex and ER␣ during transcription activation of pS2/TFF1 by IGF-I. IGF-I stimulation induces rapid phosphorylation and an increase in protein levels of the AP1 complex. Binding of the phosphorylated AP1 complex to the pS2/TFF1 promoter allows recruitment of the chromatin remodeling factor Brg1 followed by binding of ER␣ via its interaction with c-Jun.Control of breast cancer cell proliferation is a complex, multifactorial, and interactive process. Estradiol, a steroid hormone, which acts via its nuclear receptors (ER␣ 2 and -␤ for estrogen receptor ␣ and ␤) and growth factors such as insulinlike growth factor I (IGF-I) or IGF-II, epidermal growth factor, or transforming growth factor ␣, whose action is mediated by tyrosine kinase transmembrane receptors, controls gene expression and cellular proliferation of breast cancer cells (1). Although it was discovered more than 10 years ago that ER␣ could be activated in a ligand-independent fashion by growth factors like epidermal growth factor or IGF (2), the cross-talk between estrogens and growth factor pathways remains to be elucidated.In the classical model of ER action, the receptor binds as a homodimer (3) or a heterodimer (4 -7) to estrogen response elements (EREs) within the promoters of estrogen-responsive genes. Once present on the promoter of estrogen responsive genes, ER recruits an array of transcriptional cofactors (coactivators and corepressors) that bind to the receptor and interact with other transcription factors, including components of the general transcription machinery. Some of these cofactors possess chromatin-remodeling activities or histone modifying activities or recruit additional proteins to the complex to mediate transcription (for review, see Ref. 8). ER␣ may also modulate transcription without receptor-DNA interaction by functional interference with other transcription factors such as activating protein-1 (AP1) (for review, see Refs. 9 -12).The AP1 complex, which is implicated in diverse cellular processes, including differentiation, c...

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