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®), 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.
authors.affiliation: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Dyrlægevej 88, 1, 1870, Frederiksberg C, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Bjerre
authors.forename: Lena
authors.initials: L
authors.lastname: Vinther
authors.forename: Kirstine C
authors.initials: KC
authors.lastname: Belling
authors.forename: Sidse Ø
authors.initials: SØ
authors.lastname: Würtz
authors.forename: Rachita
authors.initials: R
authors.lastname: Yadav
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lademann
authors.forename: Olga
authors.initials: O
authors.lastname: Rigina
authors.forename: Khoa Nguyen
authors.initials: KN
authors.lastname: Do
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Ditzel
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Henrik Bjørn
authors.initials: HB
authors.lastname: Nielsen
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Ramneek
authors.initials: R
authors.lastname: Gupta
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Schrohl
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells / Q000378:metabolism; D016000:Cluster Analysis; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020411:Oligonucleotide Array Sequence Analysis; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: D011980:Receptors, Progesterone; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077267:Fulvestrant; D004958:Estradiol