TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression
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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; Würtz, Sidse Ørnbjerg; Yadav, Rachita; Lademann, Ulrik Axel; Rigina, Olga; Do, Khoa Nguyen; Ditzel, Henrik Jørn; Lykkesfeldt, Anne Elisabeth; Wang, Jun; Nielsen, Henrik Bjørn; Brünner, Nils; Gupta, Ramneek; Rasmussen, Anne-Sofie Schrohl; Stenvang, Jan.
In: Tumor Biology, Vol. 34, No. 6, 2013, p. 3839-3851.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
Y1 - 2013
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
VL - 34
SP - 3839
EP - 3851
JO - Tumor Biology
JF - Tumor Biology
SN - 1010-4283
IS - 6
ER -
ID: 59312382