TIMP-1 over-expression confers resistance of MCF-7 breast cancer cells to fulvestrant Lena Vinther1, Christina Bjerre1, Kirstine Belling2, Anne-Sofie Schrohl Rasmussen1, Jian Li3,4, Xue Lin3,4, Zujing Han4, Jun Wang4, Lars Bolund3,4, Vibeke Jensen1, Birgitte Sander Nielsen1, Rolf Søkilde5, Ramneek Gupta2, Ulrik Lademann1, Nils Brünner1 and Jan Stenvang1 Sino-Danish Breast Cancer Research Centre 1Faggruppen for Patobiologi, Institut for Veterinær Sygdomsbiologi, Det Biovidenskabelige Fakultet, Københavns Universitet, Dyrlægevej 88, 1., 1870 Frederiksberg C 2 Center for Biologisk Sekvens Analyse, Institut for Systembiologi, Danmarks Tekniske Universitet, Kemitorvet, bygning 208, 2800 Lyngby 3 Institut for Human Genetik, Aarhus Universitet, Wilhelm Meyers Allé 4, 8000 Aarhus C 4 BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen 518083, China 5 Exiqon A/S, Skelstedet 16, 2950 Vedbæk Background: Endocrine resistance represents a major challenge in the management of estrogen receptor (ER) positive breast cancer. Currently no predictive biomarkers for endocrine resistance in ER-positive breast cancer patients are in clinical use. In a clinical study, patients with metastatic breast cancer and high levels of serum Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) had less benefit from endocrine therapy than patients with a lower level of serum TIMP-1 . Therefore, we evaluated the association between TIMP-1 and response to endocrine therapy using an in vitro approach. Materials and Methods: MCF-7 cells were stably transfected with pcDNA3.1(Hyg)-TIMP-1 plasmid, and a panel of subclones with different expression levels of TIMP-1 was generated. TIMP- 1 expression levels were confirmed using enzyme-linked immunosorbent assay (ELISA). We selected four subclones with high or low TIMP-1 expression and analyzed the growth response to estrogen, 4-hydroxytamoxifen and fulvestrant. These four subclones were analyzed for protein expression by western blotting, genome-wide microRNA (miRNA) expression by microarray analysis and transcriptomic changes by paired-end Solexa sequencing. Results: High expression of TIMP-1 was associated with resistance to fulvestrant, whereas growth response to 4-hydroxytamoxifen was independent of TIMP-1 expression levels. High expression of TIMP-1 protein and mRNA was associated with undetectable levels of progesterone receptor (PgR) protein and mRNA whereas ER protein and mRNA were still detected. Furthermore, TIMP-1 was induced by estradiol. In the miRNA analysis, we identified three differentially expressed miRNAs and one of these miRNAs appears to be of special interest to the above mentioned data. Conclusion: Our data suggest that a high expression of TIMP-1 in vitro is associated with resistance to fulvestrant but not to 4-hydroxytamoxifen. High expression of TIMP-1 is furthermore associated with loss of PgR but not ER.
 Lipton, A et al: Serum TIMP-1 and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen in Metastatic Breast Cancer J Clin Oncol 2008; 26;(16); 2653-8
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