DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity - PubMed (original) (raw)

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DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity

Nanyue Chen et al. Cancer Res. 2014.

Abstract

Elucidation of the regulatory controls on epithelial plasticity is pivotal not only to better understand the nature of metastasis but also for the design of targeted therapies to prevent the earliest steps in migration and invasion from the primary tumor. This review will highlight the role of the novel TRIM protein DEAR1 (annotated as TRIM62) in the regulation of apical-basal polarity and acinar morphogenesis as well as its function as a chromosome 1p35 tumor suppressor and negative regulator of TGFβ-driven epithelial-mesenchymal transition (EMT). DEAR1 binds to and promotes the ubiquitination of SMAD3, the major effector of TGFβ-mediated EMT, as well as downregulates SMAD3 targets SNAIL1/2, master transcriptional regulators of EMT. Cumulative results suggest a novel paradigm for DEAR1 in the regulation of the breast tumor microenvironment, polarity, and EMT. Because DEAR1 undergoes loss-of-function mutations, homozygous deletion, as well as copy-number losses in multiple epithelial cancers, including breast cancer, DEAR1 has clinical use as a predictive and prognostic biomarker as well as for stratifying breast cancers and potentially other epithelial tumor types for targeted therapies aimed at the pathways regulated by DEAR1.

©2014 American Association for Cancer Research.

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Figures

Figure 1

Figure 1. DEAR1 Regulates Cell polarity and Acinar Morphogenesis

Wild type DEAR1 Human mammary epithelial cells (HMECs) undergo acinar morphogenesis in 3D culture in which individual acini are formed containing a polarized layer of luminal epithelial cells surrounded by myoepithelial cells and an intact basement membrane as well as a hollow lumen formed by anoikis; with DEAR1 stable knockdown, HMECs lose apical basal polarity and proper lumen formation (figure adapted from Lott, et.al. Plos Medicine, (24)). In lower panel, introduction of wild type DEAR1 into the 21MT breast cancer cell line containing a missense mutation in DEAR1 rescued acinar morphogenesis.

Figure 2

Figure 2. DEAR1 Regulates Epithelial Plasticity by Inhibiting the TGFβ/SMAD3 pathway

Normal DEAR1 expression promotes the fine regulation of SMAD3 and inhibits TGFβ-induced EMT-associated gene expression in HMECs, while loss of function of DEAR1 by genetic alterations, such as mutation, copy number alteration or loss of expression, results in loss of polarity, a dramatic increase of SMAD3 levels, and in the presence of TGFβ, the initiation of EMT.

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