Related Experiment Video

Updated: May 4, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

13.1K

Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis

Jianfei Xue, Xia Lin, Wen-Tai Chiu

    The Journal of Clinical Investigation
    |January 3, 2014
    PubMed

    Insights

    Forkhead box M1 (FOXM1) sustains SMAD complex activation in breast cancer cells, promoting metastasis. This oncogene interacts with SMAD3, stabilizing the complex and enhancing TGF-β signaling crucial for cancer invasion.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cell Signaling

    Background:

    • Sustained SMAD complex activation in the nucleus is key to TGF-β signaling in cancer.
    • The specific drivers of SMAD activation remain poorly understood.

    Purpose of the Study:

    • To elucidate the role of oncogene FOXM1 in regulating SMAD activation and TGF-β signaling in breast cancer.
    • To investigate the interaction between FOXM1 and SMAD proteins in the context of cancer metastasis.

    Main Methods:

    • Utilized human and mouse breast cancer cell lines.
    • Investigated protein-protein interactions using co-immunoprecipitation and identified molecular mechanisms involving ubiquitination.
    • Assessed transcriptional activity, gene expression, and cellular invasion assays.
    • Correlated FOXM1 and TGF-β signaling markers with patient metastasis data.

    Main Results:

    • Oncogene FOXM1 directly interacts with SMAD3, stabilizing the SMAD3/SMAD4 complex in the nucleus by preventing TIF1γ-mediated ubiquitination.
    • Loss of FOXM1 abrogated TGF-β-induced SMAD3/SMAD4 complex formation and downstream transcriptional activity.
    • FOXM1/SMAD3 interaction is essential for TGF-β-induced breast cancer cell invasion, mediated by SLUG upregulation.
    • FOXM1 promotes metastasis independently of its transcriptional activity, and SMAD3 knockdown diminishes FOXM1-induced metastasis.
    • Elevated FOXM1 levels correlate with activated TGF-β signaling and increased metastasis in human breast cancer specimens.

    Conclusions:

    • FOXM1 promotes breast cancer metastasis by enhancing nuclear retention and stability of SMAD3/SMAD4 complexes, thereby activating TGF-β signaling.
    • Identified a critical crosstalk between FOXM1 and the TGF-β/SMAD3 pathway in driving cancer progression and metastasis.

    More Related Videos

    Spheroid Assay to Measure TGF-β-induced Invasion09:18

    Spheroid Assay to Measure TGF-β-induced Invasion

    Published on: November 16, 2011

    20.8K
    Live Cell Imaging of the TGF- β/Smad3 Signaling Pathway In Vitro and In Vivo Using an Adenovirus Reporter System11:06

    Live Cell Imaging of the TGF- β/Smad3 Signaling Pathway In Vitro and In Vivo Using an Adenovirus Reporter System

    Published on: July 30, 2018

    8.7K

    Related Concept Videos

    TGF - β Signaling Pathway01:16

    TGF - β Signaling Pathway

    The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
    7.2K
    mTOR Signaling and Cancer Progression03:03

    mTOR Signaling and Cancer Progression

    The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
    The mTOR pathway or the...
    3.6K
    mTOR Signaling and Cancer Progression03:03

    mTOR Signaling and Cancer Progression

    1.5K
    Metastasis02:30

    Metastasis

    Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.
    Epithelial-to-Mesenchymal Transition
    The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
    5.4K
    The Tumor Microenvironment02:17

    The Tumor Microenvironment

    Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
    6.3K
    Mitogens and the Cell Cycle02:38

    Mitogens and the Cell Cycle

    Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
    6.3K