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TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression

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Tumor Biology

Abstract

High levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP1) are associated with poor prognosis, reduced response to chemotherapy, and, potentially, also poor response to endocrine therapy in breast cancer patients. Our objective was to further investigate the hypothesis that TIMP1 is associated with endocrine sensitivity. We established a panel of 11 MCF-7 subclones with a wide range of TIMP1 mRNA and protein expression levels. Cells with high expression of TIMP1 versus low TIMP1 displayed significantly reduced sensitivity to the antiestrogen fulvestrant (ICI 182,780, Faslodex®), while TIMP1 levels did not influence the sensitivity to 4-hydroxytamoxifen. An inverse correlation between expression of the progesterone receptor and TIMP1 was found, but TIMP1 levels did not correlate with estrogen receptor levels or growth-promoting effects of estrogen (estradiol, E2). Additionally, the effects of fulvestrant, 4-hydroxytamoxifen, or estrogen on estrogen receptor expression were not associated with TIMP1 levels. Gene expression analyses revealed associations between expression of TIMP1 and genes involved in metabolic pathways, epidermal growth factor receptor 1/cancer signaling pathways, and cell cycle. Gene and protein expression analyses showed no general defects in estrogen receptor signaling except from lack of progesterone receptor expression and estrogen inducibility in clones with high TIMP1. The present study suggests a relation between high expression level of TIMP1 and loss of progesterone receptor expression combined with fulvestrant resistance. Our findings in vitro may have clinical implications as the data suggest that high tumor levels of TIMP1 may be a predictive biomarker for reduced response to fulvestrant.

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Conflicts of interest

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Funding and acknowledgments

This work was financially supported by the Danish National Research Foundation, A Race Against Breast Cancer, The Danish Cancer Society, and “Fonden til fremme af klinisk eksperimentel cancerforskning specielt vedrørende cancer mammae”. Anne-Sofie Schrohl is supported by The Danish Council for Independent Research, Medical Sciences.

Laurent Gautier (senior researcher, PhD, engineer, head of DTU Multi-Assay Core), Vibeke Jensen and Birgitte Sander Nielsen (technicians, Institute of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, and Sino-Danish Breast Cancer Research Centre), and Gertrud Elisabeth Krarup (centre coordinator, Sino-Danish Breast Cancer Research Centre) are all thanked for their valuable contributions.

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Authors and Affiliations

  1. Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Dyrlægevej 88, 1, 1870, Frederiksberg C, Denmark

    Christina Bjerre, Lena Vinther, Sidse Ø. Würtz, Ulrik Lademann, Nils Brünner, Anne-Sofie Schrohl & Jan Stenvang

  2. Sino-Danish Breast Cancer Research Centre, Dyrlægevej 88, 1, 1870, Frederiksberg C, Denmark

    Christina Bjerre, Lena Vinther, Kirstine C. Belling, Rachita Yadav, Ulrik Lademann, Olga Rigina, Henrik J. Ditzel, Jun Wang, Nils Brünner, Ramneek Gupta, Anne-Sofie Schrohl & Jan Stenvang

  3. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet Building 208, 2800, Lyngby, Denmark

    Kirstine C. Belling, Rachita Yadav, Olga Rigina, Henrik Bjørn Nielsen & Ramneek Gupta

  4. DTU Multiassay Core (DMAC), Technical University of Denmark, Kemitorvet Building 208, 2800, Lyngby, Denmark

    Khoa Nguyen Do

  5. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsløws Vej 21-25, 5000, Odense, Denmark

    Henrik J. Ditzel

  6. Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Henrik J. Ditzel

  7. Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen Ø, Denmark

    Anne E. Lykkesfeldt

  8. BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China

    Jun Wang

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  1. Christina Bjerre
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Correspondence to Jan Stenvang.

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CB, LV, and KCB contributed equally to this work and should be regarded as joint first authors. ASR and JS contributed equally and should be regarded as joint senior authors.

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Bjerre, C., Vinther, L., Belling, K.C. et al. TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression. Tumor Biol. 34, 3839–3851 (2013). https://doi.org/10.1007/s13277-013-0969-7

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