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Deregulation of Estrogen Receptor Coactivator Proline-, Glutamic Acid-, and Leucine-Rich Protein-1/Modulator of Nongenomic Activity of Estrogen Receptor in Human Endometrial Tumors

Department of Molecular and Cellular Oncology (R.K.V., S.B., R.K.) and Department of Pathology (R.R.B.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Center for Biotechnology (J.-Å.G.), Karolinska Institute, Novum, S-14157 Huddinge, Sweden

Address all correspondence and requests for reprints to: Ratna K. Vadlamudi, Department of Genetics, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70005. E-mail: rvadla{at}LSUHSC.edu; or Rakesh Kumar, Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Box 108, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: rkumar{at}mdanderson.org.

Proline-, glutamic acid-, and leucine-rich protein-1)PELP1/MNAR [modulator of nongenomic activity of estrogen receptor (ER)], a novel coregulatory protein, modulates genomic as well as nongenomic activity of ERs. We characterized the expression and localization of PELP1 in both benign and cancerous endometrium. Our results suggest that PELP1 is expressed in all stages of endometrium; however, this protein exhibits distinct localization depending on the phase. PELP1 is expressed in both the stroma and epithelial cells. Using the Ishikawa endometrial cancer model cell line and ER subtype-specific ligands, we found that PELP1 functionally interacts with both ER and ERß and enhances their transcriptional responses. However, in endometrial cancer cells, endogenous PELP1 is also required for optimal ligand-mediated transcription and proliferation responses. PELP1 promoted a tamoxifen-mediated agonistic action in endometrial, but not in breast cancer cells. PELP1 expression and localization are widely deregulated in endometrial cancers. In addition, PELP1 and ERß were localized predominantly in the cytoplasm of high-grade endometrial tumors. Our results suggest that PELP1 plays an essential role in the proliferation of cancerous endometrial cells.

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