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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 β-catenin/TCF signaling, which was visualized using both β-catenin immunohistochemistry and the β-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, ΔNPEA3En. Expression of ΔNPEA3En 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 ΔNPEA3En transgene was profoundly reduced in mammary tumors compared to nontumorous mammary glands from bigenic MMTV/ Wnt1 , MMTV/ΔNPEA3En 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.

Pea3 Transcription Factors and Wnt1-Induced Mouse Mammary Neoplasia