Genome-wide, computational approaches are powerful tools in identifying key regulatory and developmental pathways that contribute to transcriptional dysregulation during breast cancer onset and disease progression. The ETS transcription factor ELF5 is a master regulator of the alveolar lineage and plays a key role in controlling cell-fate of luminal progenitors in the mammary gland. We have developed human and mouse models to investigate the role of ELF5 in breast cancer. Using transcript profiling and ELF5 ChIP-Seq an extensive map has been generated of the transcriptional regulatory networks controlled by ELF5 in estrogen receptor positive, luminal, breast cancers. These have shown that forced ELF5 expression in luminal breast cancer models drives a shift towards the estrogen insensitive and poor-prognosis basal-like and claudin-low molecular subtypes and provided evidence that ELF5 underpins acquisition of anti-estrogen resistance in MCF-7 cells. We have also shown that prolonged Elf5 expression, during tumour development and progression, in the PyMT mouse model of breast cancer results in a massive increase in lung metastasis and an accompanying inflammatory phenotype that strongly resembles the molecular signature of involution in the developing mammary gland. To investigate the clinical implications of these observations, the TCGA cohort was used to show that a number of the key ELF5 driven regulatory pathways, such as estrogen responsiveness, immune system activation, interferon response and inflammation, also correlated with increased ELF5 expression in the Luminal A subtype. This work highlights the use of genome-wide, computational approaches to identify transcriptional regulatory networks driven by ELF5 in luminal breast cancers.