title: Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer.
abstract: A serious obstacle to successful treatment of estrogen receptor (ER)-positive human breast cancer is cell resistance to tamoxifen (TAM) therapy. Here we show that the electrophile disulfide benzamide (DIBA), an ER zinc finger inhibitor, blocks ligand-dependent and -independent cell growth of TAM-resistant breast cancer in vitro and in vivo. Such inhibition depends on targeting disruption of the ER DNA-binding domain and its communication with neighboring functional domains, facilitating ERalpha dissociation from its coactivator AIB1 and concomitant association with its corepressor NCoR bound to chromatin. DIBA does not affect phosphorylation of HER2, MAPK, AKT, and AIB1, suggesting that DIBA-modified ERalpha may induce a switch from agonistic to antagonistic effects of TAM on resistant breast cancer cells.
authors.affiliation: Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA. lhwang@ncifcrf.gov
authors.forename: Li Hua
authors.initials: LH
authors.lastname: Wang
authors.forename: Xiao Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Han-Jong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Huang
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: John K
authors.initials: JK
authors.lastname: Inman
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020218:Response Elements; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D004247:DNA; D047628:Estrogen Receptor alpha; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C037689:benzamide