title: Overcoming resistance to fulvestrant (ICI182,780) by downregulating the c-ABL proto-oncogene in breast cancer.
abstract: Inhibiting estrogen receptor (ER) function with specific estrogen receptor modulators (SERM) can achieve a primary response in cancer patients; however, intrinsic or subsequently acquired resistance to the therapy remains a major obstacle in treatment. The pure anti-estrogen fulvestrant has been shown to be a promising antagonist of ERα in treating advanced breast cancer. However, our knowledge of the mechanisms governing cellular responsiveness to this agent is limited. Here we show that down-regulation of the nonreceptor tyrosine kinase c-ABL enhanced sensitization to fulvestrant in breast cancer cells. Blocking c-ABL kinase activity with the inhibitor imatinib further increased ERα downregulation induced by fulvestrant, decreased the number of proliferating cells entering the cell cycle, and increased cellular sensitivity to fulvestrant treatment. Conversely, introducing kinase-activated c-ABL can rescue fulvestrant-induced ERα downregulation. Consistent with the effects of imatinib, the silencing of endogenous c-ABL increased the sensitivity of breast cancer cells to fulvestrant treatment. These results demonstrate a role for c-ABL in mediating resistance to the pure anti-estrogen fulvestrant.
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, USA.
authors.forename: Huajun
authors.initials: H
authors.lastname: Zhao
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Lo
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Wang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001549:Benzamides; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D000077267:Fulvestrant; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C000715470:MAS1 protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D000077267:Fulvestrant; D004958:Estradiol; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl