The role of the PEA3 subfamily of
Ets transcription factors in breast
neoplasia is controversial. Although overexpression of PEA3 (E1AF/ETV4), and of the related factors ERM (ETV5) and ER81 (ETV1), have been observed in human and mouse
breast tumors, PEA3 factors have also been ascribed a
tumor suppressor function. Here, we utilized the MMTV/Wnt1 mouse strain to further interrogate the role of PEA3
transcription factors in mammary
tumorigenesis based on our previous observation that Pea3 is highly expressed in MMTV/Wnt1 mammary
tumors. Pea3 expression in mouse mammary tissues was visualized using a Pea3(NLSlacZ) reporter strain. In normal mammary glands, Pea3 expression is predominantly confined to myoepithelial cells. Wnt1 transgene expression induced marked amplification of this cell compartment in nontumorous mammary glands, accompanied by an apparent increase in Pea3 expression. The pattern of Pea3 expression in MMTV/Wnt1 mammary glands recapitulated the cellular profile of activated
beta-catenin/TCF signaling, which was visualized using both
beta-catenin immunohistochemistry and the
beta-catenin/TCF-responsive reporter Axin2(NLSlacZ). To test the requirement for PEA3 factors in Wnt1-induced
tumorigenesis, we employed a mammary-targeted dominant negative PEA3 transgene, DeltaNPEA3En. Expression of DeltaNPEA3En delayed early-onset
tumor formation in MMTV/Wnt1 virgin females (P = 0.03), suggesting a requirement for PEA3 factor function for Wnt1-driven
tumor formation. Consistent with this observation, expression of the DeltaNPEA3En transgene was profoundly reduced in mammary
tumors compared to nontumorous mammary glands from bigenic MMTV/Wnt1, MMTV/DeltaNPEA3En mice (P = 0.01). Our data provide the first description of Wnt1-mediated expansion of the Pea3-expressing myoepithelial compartment in nontumorous mammary glands. Consistent with this observation, mammary myoepithelium was selectively responsive to Wnt1. Together these data suggest the MMTV/Wnt1 strain as a potential model of basal
breast cancer. Furthermore, this study provides evidence for a protumorigenic role of PEA3 factors in breast
neoplasia, and supports targeting the
PEA3 transcription factor family in
breast cancer.