Teissedre Brigitte, Pinderhughes Alicia, Incassati Angela, Hatsell Sarah J, Hiremath Minoti, Cowin Pamela
Departments of Cell Biology and Dermatology, New York University School of Medicine, New York, New York, United States of America.
PLoS One. 2009;4(2):e4537. doi: 10.1371/journal.pone.0004537. Epub 2009 Feb 19.
Canonical Wnt/beta-catenin signaling regulates stem/progenitor cells and, when perturbed, induces many human cancers. A significant proportion of human breast cancer is associated with loss of secreted Wnt antagonists and mice expressing MMTV-Wnt1 and MMTV-DeltaN89beta-catenin develop mammary adenocarcinomas. Many studies have assumed these mouse models of breast cancer to be equivalent. Here we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin transgenes induce tumors with different phenotypes. Using axin2/conductin reporter genes we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin activate canonical Wnt signaling within distinct cell-types. DeltaN89beta-catenin activated signaling within a luminal subpopulation scattered along ducts that exhibited a K18(+)ER(-)PR(-)CD24(high)CD49f(low) profile and progenitor properties. In contrast, MMTV-Wnt1 induced canonical signaling in K14(+) basal cells with CD24/CD49f profiles characteristic of two distinct stem/progenitor cell-types. MMTV-Wnt1 produced additional profound effects on multiple cell-types that correlated with focal activation of the Hedgehog pathway. We document that large melanocytic nevi are a hitherto unreported hallmark of early hyperplastic Wnt1 glands. These nevi formed along the primary mammary ducts and were associated with Hedgehog pathway activity within a subset of melanocytes and surrounding stroma. Hh pathway activity also occurred within tumor-associated stromal and K14(+)/p63(+) subpopulations in a manner correlated with Wnt1 tumor onset. These data show MMTV-Wnt1 and MMTV-DeltaN89beta-catenin induce canonical signaling in distinct progenitors and that Hedgehog pathway activation is linked to melanocytic nevi and mammary tumor onset arising from excess Wnt1 ligand. They further suggest that Hedgehog pathway activation maybe a critical component and useful indicator of breast tumors arising from unopposed Wnt1 ligand.
经典Wnt/β-连环蛋白信号传导调节干细胞/祖细胞，一旦受到干扰，就会诱发多种人类癌症。相当一部分人类乳腺癌与分泌型Wnt拮抗剂的缺失有关，并且表达MMTV-Wnt1和MMTV-DeltaN89β-连环蛋白的小鼠会发生乳腺腺癌。许多研究认为这些乳腺癌小鼠模型是等效的。在此我们表明，MMTV-Wnt1和MMTV-DeltaN89β-连环蛋白转基因诱导出具有不同表型的肿瘤。使用axin2/传导蛋白报告基因，我们发现MMTV-Wnt1和MMTV-DeltaN89β-连环蛋白在不同细胞类型中激活经典Wnt信号传导。DeltaN89β-连环蛋白在沿导管分散的腔细胞亚群中激活信号传导，这些细胞呈现K18(+)ER(-)PR(-)CD24(高)CD49f(低)表型并具有祖细胞特性。相比之下，MMTV-Wnt1在具有两种不同干细胞/祖细胞类型特征性CD24/CD49f表型的K14(+)基底细胞中诱导经典信号传导。MMTV-Wnt1对多种细胞类型产生了额外的深远影响，这与刺猬信号通路的局部激活相关。我们记录到大型黑素细胞痣是早期增生性Wnt1腺体迄今未报道的特征。这些痣沿着乳腺主导管形成，并与黑素细胞亚群和周围基质中的刺猬信号通路活性相关。Hh信号通路活性也以与Wnt1肿瘤发生相关的方式出现在肿瘤相关基质和K14(+)/p63(+)亚群中。这些数据表明，MMTV-Wnt1和MMTV-DeltaN89β-连环蛋白在不同祖细胞中诱导经典信号传导，并且刺猬信号通路激活与黑素细胞痣以及由过量Wnt1配体引起的乳腺肿瘤发生有关。它们进一步表明，刺猬信号通路激活可能是由无拮抗作用的Wnt1配体引起的乳腺肿瘤的关键组成部分和有用指标。
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