Poster Presentation 25th Lorne Cancer Conference 2013

ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer (#179)

David Gallego Ortega 1 , Maria Kalyuga 1 , Heather J Lee 1 , Daniel Roden 1 , Mark Cawley 2 , C Elizabeth Caldon 1 , Andrew Stone 1 , Stephanie L Allerdice 1 , Fatima Valdes-Mora 1 , Rosalind Launchbury 3 , Aaron Statham 1 , Nicola Armstrong 1 , Chehani Alles 1 , Adelaide Young 4 , Andrea Egger 1 , Wendy Au 1 , Catherine Piggin 1 , Cara Evans 1 , Anita Ledger 1 , Samantha R Oakes 1 , Tilman Brummer 1 , Warren Kaplan 5 , Julia Gee 6 , Robert Nicolson 6 , Robert Sutherland 1 , Alex Swarbrick 1 , Matthew Naylor 1 , Susan Clark 1 , Jason Carroll 1 , Christopher J Ormandy 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Peter Wills Bioinformatic Center, Garvan Institute of Medical Research, Sydney, NSW, Australia
  3. Cancer Research UK, Cambridge Research Institute, Cambridge, UK
  4. University Of Bath, Bath, UK
  5. Peter Wills Bioinformatic Center, Garvan Institute of Medical Research, Sydney, NSW, Australia
  6. Breast Cancer Group, Welsh School of Pharmacy, Cardiff University, Cardiff , Wales, UK

We have previously shown that during pregnancy, expression of the ETS transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor 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 estrogen receptor positive luminal breast cancer cells and interrogated them using transcript profiling and ChIP-Seq. ELF5 supressed estrogen receptor and FOXA1 expression and broadly suppressed ERdriven 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 expression 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.