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

Christina Annette Bjerre; Lena Vinther Jensen; Kirstine Christensen Belling; Sidse Ørnbjerg Würtz; Rachita Yadav; Ulrik Axel Lademann; Olga Rigina; Khoa Nguyen Do; Henrik Jørn Ditzel; Anne Elisabeth Lykkesfeldt; Jun Wang; Henrik Bjørn Nielsen; Nils Brünner; Ramneek Gupta; Anne-Sofie Schrohl Rasmussen; Jan Stenvang

doi:10.1007/s13277-013-0969-7

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

Christina Annette Bjerre, Lena Vinther Jensen, Kirstine Christensen Belling, Sidse Ørnbjerg Würtz, Rachita Yadav, Ulrik Axel Lademann, Olga Rigina, Khoa Nguyen Do, Henrik Jørn Ditzel, Anne Elisabeth Lykkesfeldt, Jun Wang, Henrik Bjørn Nielsen, Nils Brünner, Ramneek Gupta, Anne-Sofie Schrohl Rasmussen, Jan Stenvang

11 Citations (Scopus)

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.

Original language	English
Journal	Tumor Biology
Volume	34
Issue number	6
Pages (from-to)	3839-3851
Number of pages	13
ISSN	1010-4283
DOIs	https://doi.org/10.1007/s13277-013-0969-7
Publication status	Published - Dec 2013

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Bjerre, C. A., Jensen, L. V., Belling, K. C., Würtz, S. Ø., Yadav, R., Lademann, U. A., Rigina, O., Do, K. N., Ditzel, H. J., Lykkesfeldt, A. E., Wang, J., Nielsen, H. B., Brünner, N., Gupta, R., Rasmussen, A.-S. S., & Stenvang, J. (2013). TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression. Tumor Biology, 34(6), 3839-3851. https://doi.org/10.1007/s13277-013-0969-7

TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression. / Bjerre, Christina Annette; Jensen, Lena Vinther; Belling, Kirstine Christensen et al.
In: Tumor Biology, Vol. 34, No. 6, 12.2013, p. 3839-3851.

Research output: Contribution to journal › Journal article › Research › peer-review

Bjerre, CA, Jensen, LV, Belling, KC, Würtz, SØ, Yadav, R, Lademann, UA, Rigina, O, Do, KN, Ditzel, HJ, Lykkesfeldt, AE, Wang, J, Nielsen, HB, Brünner, N, Gupta, R, Rasmussen, A-SS & Stenvang, J 2013, 'TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression', Tumor Biology, vol. 34, no. 6, pp. 3839-3851. https://doi.org/10.1007/s13277-013-0969-7

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

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{\textregistered}), 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.",

author = "Bjerre, {Christina Annette} and Jensen, {Lena Vinther} and Belling, {Kirstine Christensen} and W{\"u}rtz, {Sidse {\O}rnbjerg} and Rachita Yadav and Lademann, {Ulrik Axel} and Olga Rigina and Do, {Khoa Nguyen} and Ditzel, {Henrik J{\o}rn} and Lykkesfeldt, {Anne Elisabeth} and Jun Wang and Nielsen, {Henrik Bj{\o}rn} and Nils Br{\"u}nner and Ramneek Gupta and Rasmussen, {Anne-Sofie Schrohl} and Jan Stenvang",

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T1 - TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression

AU - Bjerre, Christina Annette

AU - Jensen, Lena Vinther

AU - Belling, Kirstine Christensen

AU - Würtz, Sidse Ørnbjerg

AU - Yadav, Rachita

AU - Lademann, Ulrik Axel

AU - Rigina, Olga

AU - Do, Khoa Nguyen

AU - Ditzel, Henrik Jørn

AU - Lykkesfeldt, Anne Elisabeth

AU - Wang, Jun

AU - Nielsen, Henrik Bjørn

AU - Brünner, Nils

AU - Gupta, Ramneek

AU - Rasmussen, Anne-Sofie Schrohl

AU - Stenvang, Jan

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

U2 - 10.1007/s13277-013-0969-7

DO - 10.1007/s13277-013-0969-7

M3 - Journal article

C2 - 23881388

SN - 1010-4283

VL - 34

SP - 3839

EP - 3851

JO - Tumor Biology

JF - Tumor Biology

IS - 6

ER -

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

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