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GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis

Oncogene volume 36, pages 5567–5575 (2017)Cite this article

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Abstract

Semaphorin 3B (SEMA3B) is a secreted axonal guidance molecule that is expressed during development and throughout adulthood. Recently, SEMA3B has emerged as a tumor suppressor in non-neuronal cells. Here, we show that SEMA3B is a direct target of GATA3 transcriptional activity. GATA3 is a key transcription factor that regulates genes involved in mammary luminal cell differentiation and tumor suppression. We show that GATA3 relies on SEMA3B for suppression of tumor growth. Loss of SEMA3B renders GATA3 inactive and promotes aggressive breast cancer development. Overexpression of SEMA3B in cells lacking GATA3 induces a GATA3-like phenotype and higher levels of SEMA3B are associated with better cancer patient prognosis. Moreover, SEMA3B interferes with activation of LIM kinases (LIMK1 and LIMK2) to abrogate breast cancer progression. Our data provide new insights into the role of SEMA3B in mammary gland and provides a new branch of GATA3 signaling that is pivotal for inhibition of breast cancer progression and metastasis.

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Acknowledgements

We acknowledge Dr Gera Neufeld for providing the SEMA3B overexpression DNA construct. We thank Dr Luca Tamagnone for his generous gift of lentiviral SEMA3B short hairpin RNA constructs. We thank Elena Atamaniuc for technical assistance. This study was supported by funds from the National Cancer Institute (R01 CA129523 and R01 CA190851 to ZW); PS was supported by an Institutional National Research Service Award (T32 CA108462); C-YW was supported by a grant from the Ministry of Science and Technology, Taiwan (104-2917-I-006-002); CH was supported by funds from the Tegger Foundation, Wenner-Gren Foundations, Sweden-America Foundation, Swedish Society of Medicine and Swedish Society for Medical Research; and HGV was supported by a Becas Chile Scholarship.

Author contributions

PS, C-YW and ZW designed the project; PS, C-YW, CH, HGV, AR and YY performed the experiments; JC contributed material; PS, C-YW and ZW analyzed and interpreted the data; M-DL provided supervision; PS, C-YW and ZW wrote the paper.

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  1. P Shahi and C-Y Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco,, CA, USA

    P Shahi, C-Y Wang, J Chou, C Hagerling, H Gonzalez Velozo, A Ruderisch, Y Yu & Z Werb

  2. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco,, CA, USA

    P Shahi

  3. Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    C-Y Wang & M-D Lai

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Shahi, P., Wang, CY., Chou, J. et al. GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis. Oncogene 36, 5567–5575 (2017). https://doi.org/10.1038/onc.2017.165

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