title: Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions.
abstract: Our previous investigations using cell models of tamoxifen resistance have shown that the acquisition of an endocrine-insensitive state is accompanied by an invasive in vitro phenotype. In this study, we wished to determine whether this was specifically related to partial oestrogen receptor agonists or whether similar phenomena arise with the newer 'pure' anti-oestrogens, exemplified by fulvestrant. Our data demonstrate that the development of fulvestrant resistance in two breast cancer cell lines, MCF7 and T47D, is accompanied by an augmented migratory and invasive phenotype in vitro and overexpression of the HGF/SF receptor, c-Met. Importantly, upregulated c-Met expression in these cells facilitates their stimulation by HGF/SF-secreting stromal fibroblasts, leading to the activation of Src, Akt and ERK1/2 and a profound enhancement of their aggressive phenotype in vitro. These effects could be specifically attributable to activation of the c-Met receptor since the inclusion of neutralising antibodies to c-Met, or siRNA-mediated knockdown of c-Met expression, suppressed both invasion and migration stimulated by either exogenous HGF/SF, fibroblast-conditioned medium or following co-culture with fibroblast cells. Together, these in vitro data suggest that the development of fulvestrant resistance in vivo may confer a metastatic advantage to the cells by allowing their migratory and invasive behaviour to be augmented by surrounding stromal cells.
authors.affiliation: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Metastasis and Angiogenesis Research Group, Department of Surgery, Cardiff University, UK. hiscoxse1@cf.ac.uk
authors.forename: Stephen
authors.initials: S
authors.lastname: Hiscox
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Jordan
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Maureen
authors.initials: M
authors.lastname: Harper
authors.forename: Richard
authors.initials: R
authors.lastname: McClelland
authors.forename: Chris
authors.initials: C
authors.lastname: Smith
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014945:Wound Healing / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077267:Fulvestrant; D004958:Estradiol; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met