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 mammary alveolar development that specifies the formation of the estrogen receptor negative (ER-) secretory lineage during pregnancy1. We have recently discovered that Elf5 acts during the specification of the basal breast cancer subtype by opposing estrogen action via direct transcriptional repression of FOXA1. This mechanism is also apparent in luminal breast cancer cells that have become resistant to anti-estrogen therapy2. 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 and the human breast cancer MDA-MB-231 cells, we demonstrate that Elf5 regulates epithelial-to-mesenchymal transition (EMT), driving an epithelial status 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 a dramatic increase of pulmonary metastases. Elf5 over-expressing tumours exhibit increased angiogenesis and hemorrhage indicating abnormal vascular reorganization. Interestingly, gene profiling shows that lactation genesets are up-regulated in Elf5 overexpressing tumour cells indicating a reminiscence function of Elf5 still acting in cancer cells, as lactation cannot proceed, involution immediately precedes with the up-regulation of involution related inflammation genesets. Neutrophil recruitment characteristic of early stages of involution is co-opted in the tumours, thus Elf5-driven chronic inflammation is associated to an expansion of pro-tumorigenic neutrophils. These neutrophils, also known as tumour infiltrating Myeloid Derived Suppressor Cells (MDSC) (CD11b+/Gr1+), consequently suppress CD8+ T-Cells inducing immune tumour tolerance, a major mechanism of tumour microenvironment-induced metastasis in PyMT tumours. We have identified lactation and inflammation signatures associated with Elf5 expression in Luminal A breast cancer patient cohorts using The Cancer Genome Atlas (TCGA) database.
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.