Function of PEA3 Ets Transcription Factors in Mammary Gland Development and Oncogenesis

The Ets gene families of mice and man currently comprise 27 genes that encode sequence-specific transcription factors. Ets proteins share an ∼85 amino acid structurally conserved ETS DNA binding domain. Genetic analyses in model organisms suggest roles for Ets proteins in embryonic development and various adult physiological processes. Chromosomal translocations involving several ETS genes are associated with Ewing's sarcomas and leukemias, whereas the overexpression of some ETS genes is linked with numerous malignancies, including breast cancer. Indeed PEA3, ETS-1, PDEF, and ELF-3 transcripts have all been reported to be elevated in human breast tumors. Some of the ETS genes that are overexpressed in human breast tumors are also overexpressed in mouse models of this disease. Notably, pea3, as well as its close paralogs er81 and erm, which comprise the pea3 subfamily of ets genes, are coordinately overexpressed in mouse mammary tumors. Genetic analyses in mice reveal required roles for one or more of the PEA3 subfamily Ets proteins in the initiation and progression of mouse mammary tumors. The pea3 subfamily genes are normally expressed in the primitive epithelium of mouse mammary buds during embryogenesis, and these three genes are expressed in epithelial progenitor cells during postnatal mammary gland development. Loss-of-function mutations in the mouse pea3 gene results in increased numbers of terminal end buds and an increased fraction of proliferating cells in these structures, suggesting a role for PEA3 in progenitor cell renewal or terminal differentiation. Taken together these observations suggest that the PEA3 subfamily proteins play key regulatory roles in both mammary gland development and oncogenesis.