Identification and Characterization of PEA3 Ets Subfamily Target Genes in Human Mammary Epithelial Cells

摘要

The human ETS gene family comprises 27 individual members and encodes sequence specific DNA binding proteins that regulate transcription. PEA3 is the founding member of a subfamily of ETS genes, which also include ER81 and ERM. PEA3 is overexpressed in 76% of all human breast tumors and in 93% of the HER2- positive subclass of such tumors. PEA3 is also overexpressed in most human breast tumor cell lines by comparison to non-transformed immortalized human mammary epithelial cells. Furthermore, PEA3 transcripts are elevated in the mammary tumors of three different breast cancer prone transgenic mouse strains and inhibition of the function of PEA3 (and ER81 and ERM) in mammary epithelial cells abrogates mammary oncogenesis induced by Her2. These findings imply that PEA3 and its subfamily members are required for mammary oncogenesis by regulating the expression of genes whose products play cardinal roles in breast cancer. Our objective is to identify PEA3 regulated genes in human mammary tumor cells; such genes may encode diagnostic and prognostic markers and molecular targets for drug discovery. To this end we constructed and characterized recombinant human adenoviruses encoding PEA3 or dominant-negative PEA3 and assessed their capacity to infect and regulated expression of cellular genes in untransformed and transformed human mammary epithelial cells.