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Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Sensitizes Breast Cancer Cells to Tumor Necrosis Factor-–Induced Apoptosis and Cell Growth Arrest

Authors' Affiliations: ¹ Institute of Immunology, Zhejiang University, Hangzhou, PR China and ² Institute of Immunology, Second Military Medical University, Shanghai, PR China

Requests for reprints: Xuetao Cao, Institute of Immunology, Zhejiang University, 353 Yanan Road, Hangzhou 310031, Zhejiang, PR China. Phone: 86-21-2507-0316; Fax: 86-571-8721-7329; E-mail: caoxt{at}public3.sta.net.cn.

Purpose: The current therapeutic approach is not so effective in breast cancer patients. Alternative treatment protocols aimed at different targets need to be explored. We recently reported a novel phosphatidylethanolamine-binding protein, human phosphatidylethanolamine-binding protein 4 (hPEBP4), as an antiapoptotic molecule. The finding led us to explore a promising approach for breast cancer therapy via silencing the expression of hPEBP4.

Experimental Design: hPEBP4 expression in clinical breast specimens was examined by Tissue Microarrays. RNA interference was used to silence hPEBP4 expression in MCF-7 breast carcinoma cells and the effects on cell proliferation, cell cycle progression, apoptosis, as well as underlying mechanisms, were investigated.

Results: hPEBP4 was found to be expressed in up to 50% of breast cancers but in only <4% of normal breast tissues. Silencing of hPEBP4 potentiated tumor necrosis factor- (TNF-)–induced apoptosis and cell cycle arrest in MCF-7 cells, which was due to the increased mitogen-activated protein kinase activation and the enhanced phosphatidylethanolamine externalization. Further investigation showed that silencing of hPEBP4 in MCF-7 cells promoted TNF--induced stability of p53, up-regulation of phospho-p53^ser15, p21^waf/cip, and Bax, and down-regulation of Bcl-2 and Bcl-xL, which were shown to depend on extracellular signal-regulated kinase 1/2 and c-jun NH₂-terminal kinase activation by hPEBP4 silencing. Moreover, the increased proportion of cells in the G₀-G₁ phase of cell cycle was observed in hPEBP4-silenced MCF-7 cells on TNF- treatment and the expression of cyclin A and cyclin E was down-regulated more significantly.

Conclusions: The antiapoptotic effect and the preferential expression pattern in breast cancer tissues make hPEBP4 a new target for breast cancer therapy. Silencing of hPEBP4 expression may be a promising approach for the treatment of breast carcinoma.

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