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 Lademan, Olga Rigina, Khoa Nguyen Do, Henrik Jørn Ditzel, Anne Elisabeth Lykkesfeldt, Jun Wang, Henrik Bjørn Nielsen, Nils Brünner, Ramneek Gupta, Anne-Sofie Schrohl, Jan Stenvang

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Abstract High levels of Tissue Inhibitor ofMetalloproteinases-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.
    Original languageEnglish
    JournalTumor Biology
    Volume34
    Pages (from-to)3839-3851
    ISSN1010-4283
    DOIs
    Publication statusPublished - 2013

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