orals International Association for Breast Cancer Research 2014

Elf5-forced lactation induces lung metastasis in the MMTV-PyMT mouse mammary tumour model   (#70)

David Gallego Ortega 1 , Anita Ledger 1 , Daniel Roden 1 , Christina Cho 1 , Stephanie L. Allerdice 1 , Heather J. Lee 2 , Fatima Valdes-Mora 1 , Adelaide I.J. Young 1 , Brian Y. Lee 1 , Warren Kaplan 3 , Robert Salomon 1 , Catherine Piggin 1 , Brian Rabinovich 4 , Ewan Millar 1 , Samantha R. Oakes 1 , Tatyana Chtanova 1 , Alexander Swarbrick 1 , Matthew Naylor 5 , Sandra O'Toole 1 , Julie M.W. Gee 6 , Ian Ellis 7 , Susan J. Clark 1 , Christopher J. Ormandy 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Epigenetics, Babraham Institute, Cambridge, UK
  3. Peter Wills Bioinformatic Center, Garvan Institute of Medical Research, Sydney, NSW, Australia
  4. MD Anderson, Houston, TX, USA
  5. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  6. Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, UK
  7. Departament of Histopathology, Nottingham City Hospital and Nottingham University, Nottingham, UK

Key pathways driving normal mammary development are often hijacked and subverted by the carcinogenic process. This is the case for the ETS transcription factor Elf5, a master regulator of lactation that specifies the formation of the estrogen receptor negative (ER-) secretory lineage during pregnancy. Elf5 acts during the specification of the basal breast cancer subtype by opposing oestrogen action, a mechanism also apparent in anti-estrogen therapy resistance cell lines. Basal and estrogen resistant breast cancers are characterised by a higher risk of metastasis and poor prognosis. 

Using our Elf5-inducible MMTV-PyMT mouse mammary tumour model, we demonstrate that Elf5 suppresses epithelial-to-mesenchymal transition (EMT), resulting in impaired cell invasion and distant seeding. At the same time, however, Elf5 orchestrates profound changes in the tumour microenvironment that largely override these cell autonomous effects, leading to an abnormal vascular reorganisation and a dramatic increase of pulmonary metastases. Lactation gene sets are enriched in Elf5 overexpressing tumour cells indicating a reminiscence function of Elf5 still acting in cancer cells; as lactation cannot proceed, involution immediately precedes with an enrichment of involution related inflammation gene sets. Myeloid recruitment characteristic of early stages of involution is co-opted in the tumours. Elf5-driven inflammation is associated to an expansion of pro-tumorigenic infiltrating Myeloid Derived Suppressor Cells (MDSC) (CD11b+/Gr1+), increasing immune tumour tolerance, a major mechanism of tumour microenvironment-induced metastasis in PyMT tumours. Similar signatures correlated with Elf5 expression in Luminal A breast cancer patient cohorts using The Cancer Genome Atlas (TCGA) database and and high cytoplasmic Elf5 expression predicts for prior prognosis in this subtype.

Our discovery indicates that an anti-ELF5 therapy may act to maintain sensitivity to antiestrogens and simultaneously suppress the metastatic phenotype in luminal A breast cancers. Patterns of Elf5 expression may provide a marker predicting antiestrogen-insensitive metastasis in luminal breast cancer.