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Updated: May 29, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Suppression of breast tumor growth and metastasis by an engineered transcription factor
Adriana S Beltran1, Angela Russo, Haydee Lara
1Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
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.
Insights
Artificial Transcription Factor 126 (ATF-126) reactivates the tumor suppressor Maspin, significantly reducing breast tumor growth and metastasis. This epigenetic reprogramming restores a dormant, normal-like gene program, offering therapeutic potential for aggressive breast cancers.
Area of Science:
- * Molecular Biology
- * Cancer Research
- * Epigenetics
Background:
- * Maspin acts as a tumor and metastasis suppressor, crucial for controlling tumor progression.
- * Maspin is typically expressed in epithelial cells but silenced epigenetically during metastatic disease.
- * Reactivating Maspin expression presents a therapeutic strategy to halt metastatic spread.
Purpose of the Study:
- * To investigate the efficacy of Artificial Transcription Factor 126 (ATF-126) in inhibiting tumor progression.
- * To assess ATF-126's ability to upregulate Maspin promoter activity and suppress metastasis in breast cancer models.
- * To identify downstream genes and microRNAs regulated by Maspin reactivation via ATF-126.
Main Methods:
- * Design and transduction of ATF-126 into aggressive triple-negative breast cancer cells (MDA-MB-231).
- * In vivo administration of Doxycycline to induce ATF expression in pre-established tumors in immunodeficient mice.
- * Genome-wide transcriptional profiling (RNA-seq) to analyze gene expression changes and identify gene signatures.
- * Comparison of transcriptional profiles between ATF-126 and Maspin cDNA induction.
Main Results:
- * ATF-126 induction resulted in a 50% reduction in tumor growth and complete abolition of tumor cell colonization.
- * Identified a 19-gene signature overlapping between ATF-126 and Maspin cDNA, indicating novel downstream targets.
- * ATF-126 and Maspin cDNA reactivated tumor-suppressive miRNAs (e.g., miR-1, miR-34) and downregulated oncogenic miRNAs (e.g., miR-10b).
- * The ATF-126 gene signature was over-represented in favorable prognostic subtypes of breast cancer (ER+ 'Normal-like' and Luminal A).
Conclusions:
- * ATF-126 effectively reduces breast tumor growth and metastatic colonization by epigenetically reactivating Maspin.
- * This reactivation restores a dormant, normal-like, and differentiated gene program, including tumor suppressor genes and miRNAs.
- * The findings suggest ATF-126 as a potential therapeutic agent for breast cancer by re-establishing endogenous tumor suppression mechanisms.
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