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J. Biol. Chem., Vol. 282, Issue 6, 3498-3506, February 9, 2007

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Insulin-like Growth Factor 1 Differentially Regulates Estrogen Receptor-dependent Transcription at Estrogen Response Element and AP-1 Sites in Breast Cancer Cells^*

Sandra Cascio, Viviana Bartella^¶, Cecilia Garofalo^¶, Antonio Russo, Antonio Giordano, and Eva Surmacz¹

From the Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia Pennsylvania 19122, the Department of Oncology, University of Palermo, Palermo, Italy 90047, and the ^¶Department of Pharmaco-Biology, University of Calabria, Cosenza, Italy 87036

Cross-talk between insulin-like growth factor 1 (IGF-1) and estrogen receptor (ER) regulates gene expression in breast cancer cells, but the underlying mechanisms remain unclear. Here, we studied how 17--estradiol (E2) and IGF-1 affect ER transcriptional machinery in MCF-7 cells. E2 treatment stimulated ER loading on the estrogen response element (ERE) in the pS2 promoter and on the AP-1 motif in the cyclin D1 promoter. On ERE, similar amounts of liganded ER were found at 1–24-h time points, whereas on AP-1, ER binding fluctuated over time. At 1 h, liganded ER was recruited to ERE together with histone acetyltransferases SRC-1 and p300, ubiquitin ligase E6-AP, histone methyltransferase Carm1 (Carm), and polymerase (pol) II. This coincided with increased histone H3 acetylation and up-regulation of pS2 mRNA levels. At the same time, E2 moderately increased cyclin D1 expression, which was associated with the recruitment of liganded ER, SRC-1, p300, ubiquitin ligase E6-AP (E6L), Mdm2, and pol II, but not other regulatory proteins, to AP-1. In contrast, at 1 h, IGF-1 increased the recruitment of the ER·SRC-1·p300·E6L·Mdm2·Carm·pol II complex on AP-1, but not on ERE, and induced cyclin D1, but not pS2, mRNA expression. Notably, ER knockdown reduced the association of ER, E6L, Mdm2, Carm, and pol II with AP-1 and resulted in down-regulation of cyclin D1 expression. IGF-1 potentiated the effects of E2 on ERE but not to AP-1 and increased E2-dependent pS2, but not cyclin D1, mRNA expression. In conclusion, E2 and IGF-1 differentially regulate ER transcription at ERE and AP-1 sites.

Received for publication, June 29, 2006 , and in revised form, December 12, 2006.

^* This work was supported by the Sbarro Health Research Organization. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Sbarro Institute for Cancer Research and Molecular Medicine College of Science and Technology, Temple University, 1900 N. 12th St., Rm. 446, Philadelphia, PA 19122. Tel.: 215-204-0306; E-mail: surmacz{at}temple.edu.

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