Estrogen receptor alpha and the activating protein-1 complex cooperate during insulin-like growth factor-I-induced transcriptional activation of the pS2/TFF1 gene.

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 alpha (ERalpha). However the precise molecular mechanisms involved in this process are still unclear. IGF-I treatment induces phosphorylation of the AF1 domain of ERalpha 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 ERalpha and for the activating protein-1 (AP1) complex, transcriptional activation by IGF-I requires both ERalpha 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 ERalpha. We propose a molecular mechanism with stepwise assembly of the AP1 complex and ERalpha 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 ERalpha via its interaction with c-Jun.