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The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Rakesh Kumar, Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-3558; Fax: 713-745-3792. E-mail: rkumar{at}mdanderson.org

Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel coregulator of the estrogen receptor that plays a role in both genomic and nongenomic actions of the estrogen receptor. Emerging studies suggest that in addition to the nuclear localization of PELP1, it is predominantly localized in the cytoplasm in human breast tumors, leading to excessive nongenomic signaling and possibly to tamoxifen resistance. The mechanisms underlying resistance to hormones in preclinical model systems remain under intense investigation. In an effort to develop a model system to treat tumor cells with cytoplasmic PELP1 expression and tamoxifen resistance, here we used the cytokine tumor necrosis factor (TNF)-. We found that clones of MCF-7 human breast cancer cells overexpressing PELP1 in the cytoplasm were distinctly sensitive to TNF--induced apoptosis than were wild-type nuclear PELP1– and pcDNA vector–expressing clones as revealed by cell growth assay, cell cycle analysis, Annexin V staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. We also found that the clones with cytoplasmic PELP1 overexpression had significantly less antiapoptotic protein Bcl-2 and nuclear factor-B DNA binding, but increased cyclin E expression, further supporting evidence that these cells are sensitive to apoptosis. The mechanism behind TNF-induced apoptosis in these cells involves caspases, as revealed by poly(ADP-ribose) polymerase cleavage and the broad-spectrum caspase inhibitor Z-VAD-inhibited apoptosis. In conclusion, our results suggest that altered localization of PELP1 promotes heightened sensitivity to TNF- in MCF-7 cells, paving the way for developing new treatment strategies for tumors with cytoplasmic PELP1 expression. [Mol Cancer Ther 2006;5(2):230–7]

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Note: The current address for R.K. Vadlamudi is Department of Genetics, Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, New Orleans, LA 70112.

Received 7/25/05; revised 11/22/05; accepted 12/16/05.

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