title: MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers.
abstract: Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Morassa
authors.initials: M
authors.lastname: Mohseni
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Justin
authors.initials: J
authors.lastname: Cidado
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Croessmann
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Karen
authors.initials: K
authors.lastname: Cravero
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cimino-Mathews
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Hong Yuen
authors.initials: HY
authors.lastname: Wong
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Rob
authors.initials: R
authors.lastname: Scharpf
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Zabransky
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Abde M
authors.initials: AM
authors.lastname: Abukhdeir
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Garay
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Wang
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Beaver
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Rory L
authors.initials: RL
authors.lastname: Cochran
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Blair
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: D Marc
authors.initials: DM
authors.lastname: Rosen
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Bracha
authors.initials: B
authors.lastname: Erlanger
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Hurley
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and.
authors.forename: Josh
authors.initials: J
authors.lastname: Lauring
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; and The Whiting School of Engineering, Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218 bpark2@jhmi.edu.
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D045643:DNA Repair Enzymes / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010641:Phenotype; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D019076:Transgenes; D016896:Treatment Outcome
chemical_list: D004967:Estrogens; C523332:MACROD2 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D013629:Tamoxifen; D006867:Hydrolases; D045643:DNA Repair Enzymes
keywords: ER positive; MACROD2; breast cancer; resistance; tamoxifen