title: Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib ('Iressa', ZD1839).
abstract: Despite an initial response to antihormonal therapies, the development of resistance will occur in a significant number of breast cancer patients. The mechanisms that underlie acquired resistance are not yet clear. Using a previously established in vitro cell model of tamoxifen resistance in MCF7 cells, shown to display autocrine epidermal growth factor receptor (EGFR) signalling, we assessed how resistance might modulate their metastatic phenotype in vitro, as metastatic disease is the single most important factor affecting the mortality of cancer patients. Furthermore, we investigated the effect of the EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839; AstraZeneca), on this behaviour. The acquisition of tamoxifen resistance in MCF7 cells was accompanied by a dramatic and significant increase in their invasive and motile nature. The affinity of these cells for matrix components was also enhanced. Inhibition of EGFR signalling with gefitinib reduced both basal and TGF-alpha-stimulated invasion and motility and reduced cell-matrix adhesion. In conclusion, we demonstrate here that resistance to tamoxifen in breast cancer cells is accompanied by a significant increase in their basal motile and invasive activity, properties associated with increased metastatic potential. Inhibition of EGFR signalling by gefitinib significantly inhibited cell motility and invasion thus suggesting a role for the EGF receptor in the aggressive phenotype of tamoxifen-resistant breast cancer cells.
authors.affiliation: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, King Edward VII Avenue, Cardiff, UK. HiscoxSE1@cf.ac.uk
authors.forename: Stephen
authors.initials: S
authors.lastname: Hiscox
authors.forename: Liam
authors.initials: L
authors.lastname: Morgan
authors.forename: Denise
authors.initials: D
authors.lastname: Barrow
authors.forename: Carol
authors.initials: C
authors.lastname: Dutkowskil
authors.forename: Alan
authors.initials: A
authors.lastname: Wakeling
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D006801:Humans; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011799:Quinazolines / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011799:Quinazolines; D013629:Tamoxifen; D000077156:Gefitinib