title: Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells.
abstract: Acquired resistance is a major problem limiting the clinical benefit of endocrine therapy. To investigate the mechanisms involved, two in vitro models were developed from MCF-7 cells. Long-term culture of MCF-7 cells in estrogen deprived medium (LTED) mimics aromatase inhibition in patients. Continued exposure of MCF-7 to tamoxifen represents a model of acquired resistance to antiestrogens (TAM-R). Long-term estrogen deprivation results in sustained activation of the ERK MAP kinase and the PI3 kinase/mTOR pathways. Using a novel Ras inhibitor, farnesylthiosalicylic acid (FTS), to achieve dual inhibition of the pathways, we found that the mTOR pathway plays the primary role in mediation of proliferation of LTED cells. In contrast to the LTED model, there is no sustained activation of ERK MAPK but enhanced responsiveness to rapid stimulation induced by E(2) and TAM in TAM-R cells. An increased amount of ERalpha formed complexes with EGFR and c-Src in TAM-R cells, which apparently resulted from extra-nuclear redistribution of ERalpha. Blockade of c-Src activity drove ERalpha back to the nucleus and reduced ERalpha-EGFR interaction. Prolonged blockade of c-Src activity restored sensitivity of TAM-R cells to tamoxifen. Our results suggest that different mechanisms are involved in acquired endocrine resistance and the necessity for individualized treatment of recurrent diseases.
authors.affiliation: Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22903, USA. wy9c@virginia.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.forename: Yuebai
authors.initials: Y
authors.lastname: Li
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use*; D004967:Estrogens / Q000378:metabolism*; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000494:pharmacology; D015854:Up-Regulation; D019061:src-Family Kinases
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D066246:ErbB Receptors; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D005204:Farnesol; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D011960:Receptors, Estrogen; D012459:Salicylates; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen; D019061:src-Family Kinases; C093323:farnesylthiosalicylic acid; C546842:MTOR protein, human; C000631346:CSK protein, human