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GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression, invadopodium formation, and breast cancer cell invasion.
J Biol Chem. 2013 Dec 27; 288(52):36971-82.JB

Abstract

Transforming growth factor β (TGFβ) is a potent and context-dependent regulator of tumor progression. TGFβ promotes the lung metastasis of basal-like (but not the luminal-like) breast cancer. Here, we demonstrated that fascin, a pro-metastasis actin bundling protein, was a direct target of the canonical TGFβ-Smad4 signaling pathway in basal-like breast cancer cells. TGFβ and Smad4 induced fascin overexpression by directly binding to a Smad binding element on the fascin promoter. We identified GATA3, a transcription factor crucial for mammary gland morphogenesis and luminal differentiation, as a negative regulator of TGFβ- and Smad4-induced fascin overexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated TGFβ- and Smad4-mediated overexpression of fascin and other TGFβ response genes, invadopodium formation, cell migration, and invasion, suggesting suppression of the canonical TGFβ-Smad signaling axis. Mechanistically, GATA3 abrogated the canonical TGFβ-Smad signaling by abolishing interactions between Smad4 and its DNA binding elements, potentially through physical interactions between the N-terminal of GATA3 and Smad3/4 proteins. Our findings provide mechanistic insight into how TGFβ-mediated cell motility and invasiveness are differentially regulated in breast cancer.

Authors+Show Affiliations

From the Department of Tumor Biology.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24235142

Citation

Sun, Jianwei, et al. "GATA3 Transcription Factor Abrogates Smad4 Transcription Factor-mediated Fascin Overexpression, Invadopodium Formation, and Breast Cancer Cell Invasion." The Journal of Biological Chemistry, vol. 288, no. 52, 2013, pp. 36971-82.
Sun J, He H, Pillai S, et al. GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression, invadopodium formation, and breast cancer cell invasion. J Biol Chem. 2013;288(52):36971-82.
Sun, J., He, H., Pillai, S., Xiong, Y., Challa, S., Xu, L., Chellappan, S., & Yang, S. (2013). GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression, invadopodium formation, and breast cancer cell invasion. The Journal of Biological Chemistry, 288(52), 36971-82. https://doi.org/10.1074/jbc.M113.506535
Sun J, et al. GATA3 Transcription Factor Abrogates Smad4 Transcription Factor-mediated Fascin Overexpression, Invadopodium Formation, and Breast Cancer Cell Invasion. J Biol Chem. 2013 Dec 27;288(52):36971-82. PubMed PMID: 24235142.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression, invadopodium formation, and breast cancer cell invasion. AU - Sun,Jianwei, AU - He,Huifang, AU - Pillai,Smitha, AU - Xiong,Yin, AU - Challa,Sridevi, AU - Xu,Liyan, AU - Chellappan,Srikumar, AU - Yang,Shengyu, Y1 - 2013/11/14/ PY - 2013/11/16/entrez PY - 2013/11/16/pubmed PY - 2014/2/22/medline KW - Breast Cancer KW - Cell Invasion KW - Cytoskeleton KW - GATA KW - Metastasis KW - SMAD Transcription Factor SP - 36971 EP - 82 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 288 IS - 52 N2 - Transforming growth factor β (TGFβ) is a potent and context-dependent regulator of tumor progression. TGFβ promotes the lung metastasis of basal-like (but not the luminal-like) breast cancer. Here, we demonstrated that fascin, a pro-metastasis actin bundling protein, was a direct target of the canonical TGFβ-Smad4 signaling pathway in basal-like breast cancer cells. TGFβ and Smad4 induced fascin overexpression by directly binding to a Smad binding element on the fascin promoter. We identified GATA3, a transcription factor crucial for mammary gland morphogenesis and luminal differentiation, as a negative regulator of TGFβ- and Smad4-induced fascin overexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated TGFβ- and Smad4-mediated overexpression of fascin and other TGFβ response genes, invadopodium formation, cell migration, and invasion, suggesting suppression of the canonical TGFβ-Smad signaling axis. Mechanistically, GATA3 abrogated the canonical TGFβ-Smad signaling by abolishing interactions between Smad4 and its DNA binding elements, potentially through physical interactions between the N-terminal of GATA3 and Smad3/4 proteins. Our findings provide mechanistic insight into how TGFβ-mediated cell motility and invasiveness are differentially regulated in breast cancer. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/24235142/GATA3_transcription_factor_abrogates_Smad4_transcription_factor_mediated_fascin_overexpression_invadopodium_formation_and_breast_cancer_cell_invasion_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=24235142 DB - PRIME DP - Unbound Medicine ER -