Loss of a negative feedback loop involving pea3 and cyclin d2 is required for pea3-induced migration in transformed mammary epithelial cells.

Abstract

UNLABELLED:

The Ets family transcription factor Pea3 (ETV4) is involved in tumorigenesis especially during the metastatic process. Pea3 is known to induce migration and invasion in mammary epithelial cell model systems. However, the molecular pathways regulated by Pea3 are still misunderstood. In the current study, using in vivo and in vitro assays, Pea3 increased the morphogenetic and tumorigenic capacity of mammary epithelial cells by modulating their cell morphology, proliferation, and migration potential. In addition, Pea3 overexpression favored an epithelial-mesenchymal transition (EMT) triggered by TGF-β1. During investigation for molecular events downstream of Pea3, Cyclin D2 (CCND2) was identified as a new Pea3 target gene involved in the control of cellular proliferation and migration, a finding that highlights a new negative regulatory loop between Pea3 and Cyclin D2. Furthermore, Cyclin D2 expression was lost during TGF-β1-induced EMT and Pea3-induced tumorigenesis. Finally, restored Cyclin D2 expression in Pea3-dependent mammary tumorigenic cells decreased cell migration in an opposite manner to Pea3. As such, these data demonstrate that loss of the negative feedback loop between Cyclin D2 and Pea3 contributes to Pea3-induced tumorigenesis.

IMPLICATIONS:

This study reveals molecular insight into how the Ets family transcription factor Pea3 favors EMT and contributes to tumorigenesis via a negative regulatory loop with Cyclin D2, a new Pea3 target gene.

• Authors: Franck Ladam, Isabelle Damour, Patrick Dumont, Zoulika Kherrouche, Yvan de Launoit, David Tulasne, Anne Chotteau-Lelievre
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 11 Pg. 1412-24 (Nov 2013) ISSN: 1557-3125 [Electronic] United States
• PMID: 23989931 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Cyclin D2
• Transcription Factors
• Transforming Growth Factor beta1
• transcription factor PEA3

Topics

• Animals
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation
• Cell Transformation, Neoplastic
• Cyclin D2 (metabolism)
• Epithelial Cells (metabolism, pathology)
• Epithelial-Mesenchymal Transition
• Feedback, Physiological
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Mammary Glands, Animal (metabolism, pathology)
• Mammary Neoplasms, Experimental (genetics, metabolism, pathology)
• Mice
• Mice, SCID
• Neoplasm Invasiveness
• Transcription Factors (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Xenograft Model Antitumor Assays