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The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

Oncogene volume 35, pages 5043–5055 (2016)Cite this article

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Abstract

Heparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis, albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3-O-sulfotransferase 3-OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3-OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in human epidermal growth factor receptor 2-positive (HER2+) sloan-kettering breast cancer (SKBR3) cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3-OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3-OST3A exerted dual activities acting as tumor-suppressor in lumA-michigan cancer foundation (MCF)-7 and triple negative-MD Anderson (MDA) metastatic breast (MB)-231 cells, or as an oncogenic factor in HER2+-SKBR3 cells. Mechanistically, fluorescence-resonance energy transfer-fluorescence-lifetime imaging microscopy experiments indicated that the effects of 3-OST3A in MCF-7 cells were mediated by altered interactions between HS and fibroblast growth factor-7 (FGF-7). Further, this interplay between HS and FGF-7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3-O-sulfation affects FGFR2IIIb-mediated signaling. Corroborating our cellular data, a clinical study conducted in a cohort of breast cancer patients uncovered that, in HER2+ patients, high level expression of 3-OST3A in tumors was associated with reduced relapse-free survival. Our findings define 3-OST3A as a novel regulator of breast cancer pathogenicity, displaying tumor-suppressive or oncogenic activities in a cell- and tumor-dependent context, and demonstrate the clinical value of the HS-O-sulfotransferase 3-OST3A as a prognostic marker in HER2+ patients.

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Acknowledgements

Dr Philippe Lassalle (INSERM U1019E11, Campus Institut Pasteur de Lille, Lille, France) is gratefully acknowledged for support with the xenograft experiments and for helpful discussion. Matthieu Chabel and Anne Robert are acknowledged for excellent technical assistance and Xiaomeng Pang is acknowledged for performing methylation analysis. This work was supported by Agence Nationale de la Recherche (ANR-GAG Network ANR-08-PCVI-0023 and ANR Meca-GT ANR-13-BSV8-0011-01), a Royal Society International Joint grant (to MWHC and SF-G), grants from Région Lorraine and Lorraine University to SF-G and to NR, and was carried out under auspices of the International Associated Laboratory (SFGEN) funded between CNRS-UL (SF-G) and University of Dundee (J-CB and MWHC). Tayside Tissue Bank is supported by Breast Cancer Campaign, Cancer Research UK (CRUK) and by NHS Tayside through the Chief Scientist Office and Health Sciences Scotland (formerly the Scottish Academic Health Science Collaboration, AHSC).

Author information

Author notes

  1. X Mao and C Gauche: These authors contributed equally to this work.

  2. M W H Coughtrie, J-C Bourdon, M Ouzzine and S Fournel-Gigleux: These authors contributed equally to this work as group leaders.

Authors and Affiliations

  1. UMR 7365 CNRS-Université de Lorraine (IMoPA), MolCelTEG Team and Glyco-Fluo platform, Biopôle, Campus Biologie-Santé, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France

    X Mao, C Gauche, C Bui, S Gulberti, F Merhi-Soussi, N Ramalanjaona, I Bertin-Jung, D Dumas, M Ouzzine & S Fournel-Gigleux

  2. Laboratory of Experimental Cancer Research, Luxembourg Institute of Health, Luxembourg, UK

    X Mao

  3. Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, UK

    M W H Coughtrie, A Diot & J-C Bourdon

  4. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

    M W H Coughtrie

  5. Cellular and Tissular Core Imaging Facility, PTIBC IBISA Nancy, Vandoeuvre-lès-Nancy, France

    D Dumas

  6. INSERM U1019E11, Lille, France

    N De Freitas Caires

  7. MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    A M Thompson

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Correspondence to S Fournel-Gigleux.

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Mao, X., Gauche, C., Coughtrie, M. et al. The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer. Oncogene 35, 5043–5055 (2016). https://doi.org/10.1038/onc.2016.44

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