Background: The PEA3 Ets transcription factor is overexpressed in the vast
majority of human breast tumors and in nearly all of those of the HER2/Neu-
positive subclass. PEA3 is also overexpressed in various transgenic mouse m
odels of this disease. Whether PEA3 plays an essential role in HER2/Neu-med
iated oncogenesis has heretofore not been addressed.
Results: Here, we report that each of the three highly related ets genes of
the pea3 subfamily (pea3, er81, and erm) were coordinately overexpressed i
n mammary tumors of MMTV-neu transgenic mice. Other ets genes normally expr
essed in the mammary gland were not upregulated in these tumors. Expression
of a dominant-negative pea3 transgene under the control of the MMTV promot
er in mammary epithelial cells of MMTV-neu transgenic mice dramatically del
ayed the onset of mammary tumors and reduced the number and size of such tu
mors in individual mice. Those tumors that arose in bitransgenic mice expre
ssed the MMTV-neu transgene, but not the MMTV-dominant-negative pea3 transg
ene,
Conclusions: These findings imply that one or more of the PEA3 subfamily Et
s proteins or other Ets proteins with related DNA binding specificity play
an essential role in Neu-mediated mammary oncogenesis. Hence, agents that i
nhibit the expression or activity of the PEA3 subfamily proteins may prove
efficacious in the treatment of breast cancer.