ELF5, normal mammary development and the heterogeneous phenotypes of breast cancer

The ETS transcription factor ELF5 specifies the formation of the secretory cell lineage of the mammary gland during pregnancy, by directing cell fate decisions of the mammary progenitor cells. The decision-making activity continues in breast cancer, where in luminal breast cancer cells forced ELF5 expression suppresses estrogen sensitivity and shifts gene expression toward the basal molecular subtype. The development of antiestrogen resistance in luminal breast cancer is accompanied by increased expression of ELF5 and acquired dependence on ELF5 for continued proliferation, providing a potential new therapeutic target or prognostic marker to improve the treatment of this stage of the disease. Forced ELF5 expression suppresses the mesenchymal phenotype, making cells more epithelial and producing lower rates of invasion and motility. Conversely, loss of ELF5 promotes metastasis, with a clear corollary in the claudin-low subtype of breast cancer, which does not express ELF5 and is highly metastatic, or during the final stages of tumor progression, where loss of ELF5 expression may be involved in the acquisition of the lethal phenotype. In circumstances where ELF5 expression increases in parallel with metastatic potential, such as anti-estrogen resistant luminal breast cancers and basal breast cancer, there is much more to be understood about ELF5 and metastasis.