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首页> 外文期刊>Molecular and Cellular Biology >The Embryonic Transcription Cofactor LBH Is a Direct Target of the Wnt Signaling Pathway in Epithelial Development and in Aggressive Basal Subtype Breast Cancers
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The Embryonic Transcription Cofactor LBH Is a Direct Target of the Wnt Signaling Pathway in Epithelial Development and in Aggressive Basal Subtype Breast Cancers

机译：胚胎转录辅因子LBH是上皮细胞发育和侵袭性基础亚型乳腺癌中Wnt信号通路的直接靶标。

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Limb-bud and heart (LBH) is a novel key transcriptional regulator of vertebrate development. However, the molecular mechanisms upstream of LBH and its role in adult development are unknown. Here we show that in epithelial development, LBH expression is tightly controlled by Wnt signaling. LBH is transcriptionally induced by the canonical Wnt pathway, as evident by the presence of conserved functional T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) binding sites in the LBH locus and rapid β-catenin-dependent upregulation of endogenous LBH by Wnt3a. In contrast, LBH induction by Wnt/β-catenin signaling is inhibited by Wnt7a, which in limb development signals through a noncanonical pathway involving Lmx1b. Furthermore, we show that LBH is aberrantly overexpressed in mammary tumors of mouse mammary tumor virus (MMTV)-Wnt1-transgenic mice and in aggressive basal subtype human breast cancers that display Wnt/β-catenin hyperactivation. Deregulation of LBH in human basal breast cancer appears to be Wnt/β-catenin dependent, as DKK1 and Wnt7a inhibit LBH expression in breast tumor cells. Overexpression studies indicate that LBH suppresses mammary epithelial cell differentiation, an effect that could contribute to Wnt-induced tumorigenesis. Taken together, our findings link LBH for the first time to the Wnt signaling pathway in both development and cancer and highlight LBH as a potential new marker for therapeutically challenging basal-like breast cancers.
机译：肢体和心脏（LBH）是脊椎动物发育的新型关键转录调节因子。但是，LBH上游的分子机制及其在成年发育中的作用尚不清楚。在这里，我们显示在上皮发育中， LBH 表达受到Wnt信号的严格控制。 LBH 由经典Wnt途径转录诱导，如 LBH <中存在保守的功能性T细胞因子（TCF）/淋巴增强因子结合因子（LEF）结合位点所证明/ em>位点和Wnt3a对内源 LBH 的快速β-catenin依赖性上调。相反，Wnt /β-catenin信号转导 LBH 受Wnt7a抑制，Wnt7a在肢体发育中通过涉及Lmx1b的非经典途径发出信号。此外，我们显示，LBH在小鼠乳腺肿瘤病毒（MMTV）- Wnt1 -转基因小鼠的乳腺肿瘤中以及在表现出Wnt /β-catenin过度活化的侵袭性基础亚型人乳腺癌中异常过表达。人基础乳腺癌中LBH的失调似乎是Wnt /β-catenin依赖性的，因为DKK1和Wnt7a抑制了乳腺癌细胞中 LBH 的表达。过度表达研究表明LBH抑制了乳腺上皮细胞的分化，这种作用可能有助于Wnt诱导的肿瘤发生。综上所述，我们的发现将LBH首次与发育和癌症中的Wnt信号通路联系起来，并突显了LBH作为治疗性基础性乳腺癌的潜在新标志物。

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