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AKT Regulation of Estrogen Receptor ß Transcriptional Activity in Breast Cancer

¹ Center for Bioenvironmental Research, ² Department of Pharmacology, ³ Department of Medicine, Section of Hematology and Medical Oncology, and ⁴ Department of Pathology, Tulane University; ⁵ Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine; ⁶ Department of Molecular Genetics, Alton Ochsner Medical Foundation, New Orleans, Louisiana and ⁷ Department of Pathology, University of Illinois College of Medicine, Chicago, Illinois

Requests for reprints: Matthew Burow, Department of Medicine-Section of Hematology and Medical Oncology, Tulane University School of Medicine, 1430 Tulane Ave. SL-78, New Orleans, LA 70112. Phone: 504-988-6688; Fax: 504-988-5483; E-mail: mburow{at}tulane.edu.

Growth factor activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been shown to activate the estrogen receptor (ER) and to mediate tamoxifen resistance in breast cancer. Here, we investigated the regulation of the transcriptional activity of the newer ERß by PI3K-AKT signaling. Tissue arrays of breast cancer specimens showed a positive association between the expressions of AKT and ERß in the clinical setting. Reporter gene assays using pharmacologic and molecular inhibitors of AKT and constitutively active AKT revealed for the first time the ability of AKT to (a) potentiate ERß activity and (b) target predominantly the activation function-2 (AF2) domain of the receptor, with a requirement for residue K269. Given the importance of coactivators in ER transcriptional activity, we further investigated the possible involvement of steroid receptor coactivator 1 (SRC1) and glucocorticoid receptor-interacting protein 1 (GRIP1) in AKT regulation of ERß. Mammalian two-hybrid assays revealed that AKT enhanced both SRC1 and GRIP1 recruitment to the ERß-AF2 domain, and reporter gene analyses revealed that AKT and GRIP1 cooperatively potentiated ERß-mediated transcription to a level much greater than either factor alone. Investigations into AKT regulation of GRIP with mammalian one-hybrid assays showed that AKT potentiated the activation domains of GRIP1 itself, and in vitro kinase assays revealed that AKT directly phosphorylated GRIP1. The cross-talk between the PI3K-AKT and ERß pathways, as revealed by the ability of AKT to regulate several components of ERß-mediated transcription, may represent an important aspect that may influence breast cancer response to endocrine therapy. (Cancer Res 2006; 66(17): 8373-81)

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