Role of Ets Transcription Factors in Mammary Gland Development and Oncogenesis

PEA3 is the founding member of a subfamily of closely related ets genes that includes ER81 and ERM. PEA3 is expressed in the epithelial cells of mammary buds at the time that these first appear during mouse embryogenesis, and it is differentially expressed during postnatal mammary gland development. PEA3 expression is highest at the onset of puberty and during early pregnancy, times of extensive epithelial outgrowth and branching. PEA3 is expressed in undifferentiated epithelial cap cells of terminal end buds, and in differentiated myoepithelial cells of ducts and alveoli. Loss-of-function mutations in the PEA3 gene compromise mammary ductal branching at the onset of puberty and early during pregnancy. PEA3 is overexpressed in the vast majority of human breast tumors and in nearly all of the HER2-positive subclass of such tumors. PEA3 is similarly overexpressed in transgenic mouse models of this malignancy. Expression of dominant-negative PEA3 in the mouse mammary gland of MMTV-HER2 transgenic mice dramatically delays the onset and reduces the incidence of mammary tumors. Hence PEA3 and/or its close relatives play key regulatory roles in both mammary gland development and oncogenesis.