The role of the ets transcription factor Elf5 in the mammary gland development has been well established. Elf5 is a hormone target; it specifies the development of the alveolar secretory epithelium during pregnancy by forcing cell fate decisions within the CD61+ progenitor population. Forced Elf5 expression in virgin mice produces a precocious development of the mammary alveoli and milk secretion. During breast carcinogenesis, Elf5 is one of the most consistently down-regulated genes, with a large loss of Elf5 expression observed in luminal cancers and more moderate loss by the basal subtype. Thus higher Elf5 expression is associated with high-grade tumours, lymphocytic infiltration and with BRCA1 mutation, reflecting the basal-luminal differences in these features. Furthermore, since the CD61+ progenitor cell is the cell of origin for basal breast cancers, a role for Elf5 in the development of basal over luminal breast cancer by forcing similar cell fate decisions, may occur.
Using an in vitro inducible model for over-expression of Elf5, we have recently demonstrated that Elf5-driven transcriptional network suppresses estrogen action, and reduces cell proliferation and tumour growth of luminal breast cancer cells. We also identified enhancement of basal subtype characteristics in these cells. In this study, we use the polyoma middle-T oncoprotein (PyMT) mouse mammary tumour model to study the effect of Elf5-overexpression in luminal subtype mammary cancer initiation and progression. Acute over-expression of Elf5 in npre-existing PyMT tumours reduced cell proliferation, as observed in human luminal models. Chronic Elf5 over-expression during carcinogenesis and progression dramatically increased the number and size of lung metastasis. Investigation of transcriptional events showed Elf5 influenced the balance between epithelial and mesenchymal phenotypes in both acute and chronic scenarios.
This study shows for the first time the role of the alveolar fate regulator Elf5 in breast cancer initiation and progression, demonstrating the role of normal developmental mechanisms in specifying the subtype of breast cancer, knowledge that will inform the development of novel therapeutic strategies.