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Suppression of Breast Tumor Growth and Metastasis by an Engineered Transcription Factor

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Title: Suppression of Breast Tumor Growth and Metastasis by an Engineered Transcription Factor
Author(s): Beltran, Adriana S.; Russo, Angela; Lara, Haydee; Fan, Cheng; Lizardi, Paul M.; Blancafort, Pilar
Abstract: Maspin is a tumor and metastasis suppressor playing an essential role as gatekeeper of tumor progression. It is highly expressed in epithelial cells but is silenced in the onset of metastatic disease by epigenetic mechanisms. Reprogramming of Maspin epigenetic silencing offers a therapeutic potential to lock metastatic progression. Herein we have investigated the ability of the Artificial Transcription Factor 126 (ATF-126) designed to upregulate the Maspin promoter to inhibit tumor progression in pre-established breast tumors in immunodeficient mice. ATF-126 was transduced in the aggressive, mesenchymal-like and triple negative breast cancer line, MDA-MB-231. Induction of ATF expression in vivo by Doxycycline resulted in 50% reduction in tumor growth and totally abolished tumor cell colonization. Genome-wide transcriptional profiles of ATF-induced cells revealed a gene signature that was found over-represented in estrogen receptor positive (ER+)‘‘Normal-like’’ intrinsic subtype of breast cancer and in poorly aggressive, ER+ luminal A breast cancer cell lines. The comparison transcriptional profiles of ATF-126 and Maspin cDNA defined an overlapping 19-gene signature, comprising novel targets downstream the Maspin signaling cascade. Our data suggest that Maspin up-regulates downstream tumor and metastasis suppressor genes that are silenced in breast cancers, and are normally expressed in the neural system, including CARNS1, SLC8A2 and DACT3. In addition, ATF-126 and Maspin cDNA induction led to the re-activation of tumor suppressive miRNAs also expressed in neural cells, such as miR-1 and miR-34, and to the down-regulation of potential oncogenic miRNAs, such as miR-10b, miR-124, and miR-363. As expected from its over-representation in ER+ tumors, the ATF-126-gene signature predicted favorable prognosis for breast cancer patients. Our results describe for the first time an ATF able to reduce tumor growth and metastatic colonization by epigenetic reactivation of a dormant, normal-like, and more differentiated gene program.
Issue Date: 2011-09-13
Publisher: Public Library of Science
Citation Info: Beltran, A. S., Russo, A., Lara, H., Fan, C., Lizardi, P. M., & Blancafort, P. 2011. Suppression of Breast Tumor Growth and Metastasis by an Engineered Transcription Factor. PLoS One, 6(9). e24595. doi:10.1371/journal.pone.0024595
Type: Article
Description: Copyright: 2011 Beltran et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited doi:10.1371/journal.pone.0024595
URI: http://hdl.handle.net/10027/8212
ISSN: 1932-6203
Sponsor: This work was supported from National Cancer Institute/National Institutes of Health grants 1R01CA125273, 3R01CA125273-03S1 and Department of Defense (DoD) W81XWH-10-1-0265 (PB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date Available in INDIGO: 2012-03-16
 

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