PMID- 16951146 OWN - NLM STAT- MEDLINE DCOM- 20071126 LR - 20101118 IS - 1538-7445 (Electronic) IS - 0008-5472 (Linking) VI - 66 IP - 17 DP - 2006 Sep 1 TI - AKT regulation of estrogen receptor beta transcriptional activity in breast cancer. PG - 8373-81 AB - Growth factor activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been shown to activate the estrogen receptor (ER) alpha and to mediate tamoxifen resistance in breast cancer. Here, we investigated the regulation of the transcriptional activity of the newer ER beta by PI3K-AKT signaling. Tissue arrays of breast cancer specimens showed a positive association between the expressions of AKT and ER beta 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 ER beta 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 ER beta. Mammalian two-hybrid assays revealed that AKT enhanced both SRC1 and GRIP1 recruitment to the ER beta-AF2 domain, and reporter gene analyses revealed that AKT and GRIP1 cooperatively potentiated ER beta-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 ER beta pathways, as revealed by the ability of AKT to regulate several components of ER beta-mediated transcription, may represent an important aspect that may influence breast cancer response to endocrine therapy. FAU - Duong, Bich N AU - Duong BN AD - Center for Bioenvironmental Research, Tulane University, New Orleans, LA, USA. FAU - Elliott, Steven AU - Elliott S FAU - Frigo, Daniel E AU - Frigo DE FAU - Melnik, Lilia I AU - Melnik LI FAU - Vanhoy, Lyndsay AU - Vanhoy L FAU - Tomchuck, Suzanne AU - Tomchuck S FAU - Lebeau, Helena P AU - Lebeau HP FAU - David, Odile AU - David O FAU - Beckman, Barbara S AU - Beckman BS FAU - Alam, Jawed AU - Alam J FAU - Bratton, Melyssa R AU - Bratton MR FAU - McLachlan, John A AU - McLachlan JA FAU - Burow, Matthew E AU - Burow ME LA - eng GR - DK059389/DK/NIDDK NIH HHS/United States GR - R06/CCR419466-02/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Estrogen Receptor beta) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Oncogene Protein v-akt) SB - IM MH - Breast Neoplasms/*genetics/metabolism/pathology MH - Cell Line MH - Estrogen Receptor beta/*genetics/metabolism MH - Female MH - Humans MH - Immunohistochemistry MH - Kidney MH - Oligonucleotide Array Sequence Analysis MH - Oncogene Protein v-akt/*metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Transcription, Genetic MH - Transfection EDAT- 2006/09/05 09:00 MHDA- 2007/12/06 09:00 CRDT- 2006/09/05 09:00 PHST- 2006/09/05 09:00 [pubmed] PHST- 2007/12/06 09:00 [medline] PHST- 2006/09/05 09:00 [entrez] AID - 66/17/8373 [pii] AID - 10.1158/0008-5472.CAN-05-3845 [doi] PST - ppublish SO - Cancer Res. 2006 Sep 1;66(17):8373-81. doi: 10.1158/0008-5472.CAN-05-3845.