Development of PEA-15 using a potent non-viral vector for therapeutic application in breast cancer.

Abstract

Advanced breast cancer requires systemic treatment, therefore developing an efficient and safe strategy is urgently needed. To ensure the success of target therapy, we have developed a breast cancer-specific construct (T-VISA) composed of the human telomerase reverse transcriptase (hTERT; T) promoter and a versatile transgene amplification vector VISA (VP16-GAL4-WPRE integrated systemic amplifier) to target PEA-15 (phosphoprotein enriched in astrocytes) in advanced breast tumors. PEA-15 contains a death effector domain that sequesters extracellular signal-regulated kinase (ERK) in the cytoplasm, thereby inhibiting cell proliferation and inducing apoptosis. T-VISA-PEA-15 was found to be highly specific, selectively express PEA-15 in breast cancer cells, and induce cancer-cell killing in vitro and in vivo without affecting normal cells. Moreover, intravenous treatment with T-VISA-PEA-15 coupled with liposome nanoparticles attenuated tumor growth and prolonged survival in mice bearing advanced breast tumors. Importantly, there was virtually no severe toxicity when PEA-15 is expressed by our T-VISA system compared with cytomegalovirus (CMV) promoter. Thus, our findings demonstrate an effective cancer-targeted therapy that is worthy of development in clinical trials eradicating advanced breast cancer.

• Authors: Xinhua Xie, Hailin Tang, Pengliu, Yanan Kong, Minqing Wu, Xiangsheng Xiao, Lu Yang, Jie Gao, Weidong Wei, Jangsoon Lee, Chandra Bartholomeusz, Naoto T Ueno, Xiaoming Xie
• Journal: Cancer letters (Cancer Lett) Vol. 356 Issue 2 Pt B Pg. 374-381 (Jan 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25304382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Intracellular Signaling Peptides and Proteins
• PEA15 protein, human
• Phosphoproteins
• TERT protein, human
• Telomerase

Topics

• Animals
• Apoptosis
• Apoptosis Regulatory Proteins
• Blotting, Western
• Breast Neoplasms (genetics, pathology, therapy)
• Cell Proliferation
• Female
• Genetic Vectors (therapeutic use)
• Humans
• Immunoenzyme Techniques
• Intracellular Signaling Peptides and Proteins (genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphoproteins (genetics)
• Promoter Regions, Genetic (genetics)
• Telomerase (genetics)
• Transgenes (genetics)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays