title: ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer.
abstract: We have previously shown that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers. To test this we constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq). ELF5 suppressed ER and FOXA1 expression and broadly suppressed ER-driven patterns of gene expression including sets of genes distinguishing the luminal molecular subtype. Direct transcriptional targets of ELF5, which included FOXA1, EGFR, and MYC, accurately classified a large cohort of breast cancers into their intrinsic molecular subtypes, predicted ER status with high precision, and defined groups with differential prognosis. Knockdown of ELF5 in basal breast cancer cell lines suppressed basal patterns of gene expression and produced a shift in molecular subtype toward the claudin-low and normal-like groups. Luminal breast cancer cells that acquired resistance to the antiestrogen Tamoxifen showed greatly elevated levels of ELF5 and its transcriptional signature, and became dependent on ELF5 for proliferation, compared to the parental cells. Thus ELF5 provides a key transcriptional determinant of breast cancer molecular subtype by suppression of estrogen sensitivity in luminal breast cancer cells and promotion of basal characteristics in basal breast cancer cells, an action that may be utilised to acquire antiestrogen resistance.
authors.affiliation: Cancer Research Program and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Kalyuga
authors.forename: David
authors.initials: D
authors.lastname: Gallego-Ortega
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Lee
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Roden
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.forename: C Elizabeth
authors.initials: CE
authors.lastname: Caldon
authors.forename: Andrew
authors.initials: A
authors.lastname: Stone
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Allerdice
authors.forename: Fatima
authors.initials: F
authors.lastname: Valdes-Mora
authors.forename: Rosalind
authors.initials: R
authors.lastname: Launchbury
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Statham
authors.forename: Nicola
authors.initials: N
authors.lastname: Armstrong
authors.forename: M Chehani
authors.initials: MC
authors.lastname: Alles
authors.forename: Adelaide
authors.initials: A
authors.lastname: Young
authors.forename: Andrea
authors.initials: A
authors.lastname: Egger
authors.forename: Wendy
authors.initials: W
authors.lastname: Au
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Piggin
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Evans
authors.forename: Anita
authors.initials: A
authors.lastname: Ledger
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Oakes
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Alexander
authors.initials: A
authors.lastname: Swarbrick
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Naylor
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
mesh_terms: D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C116038:ELF5 protein, human; D004967:Estrogens; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors