Tumor Biology

, Volume 34, Issue 6, pp 3839–3851 | Cite as

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

  • Christina Bjerre
  • Lena Vinther
  • Kirstine C. Belling
  • Sidse Ø. Würtz
  • Rachita Yadav
  • Ulrik Lademann
  • Olga Rigina
  • Khoa Nguyen Do
  • Henrik J. Ditzel
  • Anne E. Lykkesfeldt
  • Jun Wang
  • Henrik Bjørn Nielsen
  • Nils Brünner
  • Ramneek Gupta
  • Anne-Sofie Schrohl
  • Jan Stenvang
Research Article


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.


TIMP1 Fulvestrant resistance Progesterone receptor MCF-7 breast cancer cells Western blotting Gene expression 


Conflicts of interest


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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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Christina Bjerre
    • 1
    • 2
  • Lena Vinther
    • 1
    • 2
  • Kirstine C. Belling
    • 2
    • 3
  • Sidse Ø. Würtz
    • 1
  • Rachita Yadav
    • 2
    • 3
  • Ulrik Lademann
    • 1
    • 2
  • Olga Rigina
    • 2
    • 3
  • Khoa Nguyen Do
    • 4
  • Henrik J. Ditzel
    • 2
    • 5
    • 6
  • Anne E. Lykkesfeldt
    • 7
  • Jun Wang
    • 2
    • 8
  • Henrik Bjørn Nielsen
    • 3
  • Nils Brünner
    • 1
    • 2
  • Ramneek Gupta
    • 2
    • 3
  • Anne-Sofie Schrohl
    • 1
    • 2
  • Jan Stenvang
    • 1
    • 2
  1. 1.Faculty of Health and Medical Sciences, Department of Veterinary Disease BiologyUniversity of CopenhagenFrederiksberg CDenmark
  2. 2.Sino-Danish Breast Cancer Research CentreFrederiksberg CDenmark
  3. 3.Center for Biological Sequence Analysis, Department of Systems BiologyTechnical University of DenmarkLyngbyDenmark
  4. 4.DTU Multiassay Core (DMAC)Technical University of DenmarkLyngbyDenmark
  5. 5.Department of Cancer and Inflammation Research, Institute of Molecular MedicineUniversity of Southern DenmarkOdenseDenmark
  6. 6.Department of OncologyOdense University HospitalOdense CDenmark
  7. 7.Breast Cancer Group, Cell Death and MetabolismDanish Cancer Society Research CenterCopenhagen ØDenmark
  8. 8.BGI-Shenzhen, Beishan Industrial ZoneShenzhenChina

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