Abstract #1947: Role of Pea3 transcription factors in Wnt1-induced mammary tumorigenesis

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), has been observed in human and mouse breast tumors, PEA3 factors have also been ascribed a tumor suppressor function. Therefore, we utilized the MMTV/Wnt1 mouse strain to interrogate the role of PEA3 transcription factors in mammary tumorigenesis, based on our previous observation of extremely high level Pea3 expression in MMTV/Wnt1 mammary tumors. In the present study, Pea3 expression in mammary tissues was visualized using a Pea3NLSlacZ reporter strain. MMTV/Wnt1, Pea3(+/NLSlacZ) animals were generated by interbreeding Pea3(+/NLSlacZ) and MMTV/Wnt1 mice, and \#946;-galactosidase activity in mammary glands and tumors was detected by X-gal staining. In normal adult mammary glands, Pea3 expression was predominantly confined to myoepithelial cells. Mammary-targeted expression of the Wnt1 transgene caused selective amplification of this cell compartment in non-tumorous mammary glands, accompanied by an increase in Pea3 expression. In contrast, high level Pea3 expression was observed in all epithelial cells in mammary tumors. To test the requirement for PEA3 factors for Wnt1-induced tumorigenesis, we used a mouse strain expressing a mammary-targeted dominant negative PEA3 transgene \#916;NPEA3En. MMTV/Wnt1 and MMTV/\#916;NPEA3En hemizygotes were interbred, and tumor latency was compared in MMTV/Wnt1 and bigenic MMTV/Wnt1, MMTV/\#916;NPEA3En virgin female offspring. Expression of the dominant interfering mutant \#916;NPEA3En delayed early onset tumor formation in MMTV/Wnt1 virgin females (P=0.03), indicative of a requirement for PEA3 factor function for Wnt1-driven tumor formation. Consistent with this observation, expression of the \#916;NPEA3En transgene (relative to that of the Wnt1 transgene) was profoundly reduced in mammary tumors compared to non-tumorous mammary glands from bigenic MMTV/Wnt1, MMTV/\#916;NPEA3En mice. These data provide evidence for a pro-tumorigenic role of PEA3 factors in breast neoplasia, and support targeting the PEA3 transcription factor family in breast cancer. Furthermore, this study provides the first description of Wnt1-mediated amplification of the Pea3-expressing myoepithelial compartment in non-tumorous mammary glands, thus suggesting the Wnt1 transgenic strain as a potential model of basal breast cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1947.