Pea3 transcription factors and wnt1-induced mouse mammary neoplasia.
Pea3 transcription factors and wnt1-induced mouse mammary neoplasia.
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DOI：
10.1371/journal.pone.0008854
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发表时间：
2010-01-22
期刊：
影响因子：
3.7
通讯作者：
Howe LR
中科院分区：
文献类型：
--
作者：
Baker R;Kent CV;Silbermann RA;Hassell JA;Young LJ;Howe LR
ETS转录因子PEA3亚家族在乳腺肿瘤中的作用存在争议。尽管PEA3(E1AF/ETV4)及其相关因子ERM(ETV5)和Er81(ETV1)在人和小鼠乳腺肿瘤中过表达，但PEA3因子也被认为具有肿瘤抑制功能。在这里，我们利用MMTV/WNT1小鼠品系，基于我们之前观察到的PEA3在MMTV/WNT1乳腺肿瘤中高表达的观察，进一步探讨PEA3转录因子在乳腺肿瘤发生中的作用。用Pea3NLSlacZ报告菌株观察了Pea3在小鼠乳腺组织中的表达。在正常乳腺中，Pea3的表达主要局限于肌上皮细胞。WNT1转基因表达可诱导非肿瘤性乳腺组织中该细胞室的显著扩增，并伴随着Pea3表达的明显增加。β-catenin/Tcf免疫组织化学和β-catenin/tcf反应报告Axin2NLSlacZ显示了Pea3在MMTV/WNT1乳腺中的表达模式，概括了激活的β-catenin/Tcf信号的细胞轮廓。为了测试在WNT1诱导的肿瘤发生中对PEA3因子的需求，我们使用了针对乳腺的显性负性PEA3转基因基因ΔNPEA3En。ΔNPEA3En的表达延迟了MMTV/WNT1处女女性早发性肿瘤的形成(P = 0.03)，提示在WNT1驱动的肿瘤形成中需要PEA3因子的功能。与此一致的是，ΔNPEA3En转基因在乳腺肿瘤中的表达显著低于双基因MMTVWNT1、MMTVNPEA3En小鼠的非肿瘤性乳腺组织(P = 0.01)。我们的数据首次描述了WNT1介导的表达Pea3的肌上皮细胞在非肿瘤性乳腺中的扩张。与此观察一致的是，乳腺肌上皮对WNT1有选择性的反应。综上所述，这些数据表明MMTV/WNT1株可能是基础乳腺癌的模型。此外，这项研究为PEA3因子在乳腺肿瘤中的促癌作用提供了证据，并支持将PEA3转录因子家族靶向于乳腺癌。
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 Pea3NLSlacZ 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 Axin2NLSlacZ. 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.
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