Ehf controls mammary alveolar lineage differentiation and is a putative suppressor of breast tumorigenesis

The transcription factor EHF is highly expressed in the lactating mammary gland, but its role in mammary development and tumorigenesis is not fully understood. Utilizing a mouse model of Ehf deletion, herein, we demonstrate that loss of Ehf impairs mammary lobuloalveolar differentiation at late pregnancy, indicated by significantly reduced levels of milk genes and milk lipids, fewer differentiated alveolar cells, and an accumulation of alveolar progenitor cells. Further, deletion of Ehf increased proliferative capacity and attenuated prolactin-induced alveolar differentiation in mammary organoids. Ehf deletion also increased tumor incidence in the MMTV-PyMT mammary tumor model and increased the proliferative capacity of mammary tumor organoids, while low EHF expression was associated with higher tumor grade and poorer outcome in luminal A and basal human breast cancers. Collectively, these findings establish EHF as a non-redundant regulator of mammary alveolar differentiation and a putative suppressor of mammary tumorigenesis. [Display omitted] •The transcription factor EHF is essential for mammary development in pregnancy•Ehf drives differentiation of progenitor cells into milk-producing alveolar cells•Ehf deletion increased tumor development in the mouse mammary gland Nightingale and Reehorst et al. identify a key role for the transcription factor EHF in mouse mammary gland development and in controlling the differentiation of mammary epithelial cells into milk-producing cells during pregnancy. They also show that Ehf is an important suppressor of tumor development in this tissue.