title: Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance.
abstract: The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.
  
  
  
  AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR.
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Sandro Pitigliani Medical Oncology Unit and Translational Research Unit, Oncology Department, Hospital of Prato, Prato, Italy. rschiff@bcm.edu lmalorni@uslcentro.toscana.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Malorni
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giuliano
authors.affiliation: Sandro Pitigliani Medical Oncology Unit and Translational Research Unit, Oncology Department, Hospital of Prato, Prato, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Migliaccio
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Center-University Health Network, Ontario Institute for Cancer Research and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Fu
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Department of Radiology, St. James's Hospital, Dublin, Ireland.
authors.forename: Nuala
authors.initials: N
authors.lastname: Healy
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: De Angelis
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mazumdar
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas.
authors.forename: Meghana V
authors.initials: MV
authors.lastname: Trivedi
authors.affiliation: Department of Medicine and Stanford Cancer Institute, Stanford University, Stanford, California.
authors.forename: Suleiman
authors.initials: S
authors.lastname: Massarweh
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Pathology, Baylor College of Medicine, Houston, Texas.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gutierrez
authors.affiliation: Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: De Placido
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rinath
authors.initials: R
authors.lastname: Jeselsohn
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. rschiff@bcm.edu lmalorni@uslcentro.toscana.it.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics*; D013629:Tamoxifen / Q000008:administration & dosage* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; D013629:Tamoxifen; D004958:Estradiol