Mammary Tumor Regression Elicited by Wnt Signaling Inhibitor Requires IGFBP5
Mammary Tumor Regression Elicited by Wnt Signaling Inhibitor Requires IGFBP5
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DOI：
10.1158/0008-5472.can-11-3668
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Sakanaka, Chie
中科院分区：
文献类型：
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作者：
Liu, Bob Y.;Soloviev, Irina;Sakanaka, Chie
WNT配体驱动的肿瘤生长可被可溶性WNT抑制剂Fzd8CRD抑制，但其作用机制尚不清楚。在MMTV-WNT1小鼠模型中，Fzd8CRD治疗乳腺肿瘤的消退与胰岛素样生长因子(IGF)结合蛋白Igfbp5的急性和强烈诱导相吻合，IGF信号拮抗剂IGF信号拮抗剂在仔鼠断奶后介导雌性乳腺退缩。在本研究中，我们表明抑制IGF抑制通路对Wnt驱动的乳腺肿瘤的生长至关重要。我们发现，Igfbp5的调节是由β-连环素依赖的Wnt途径介导的。WNT除了IGF配体外，还通过肿瘤细胞间的旁分泌通讯促进肿瘤生长。此外，Fzd8CRD在正常乳腺退缩过程中引起Igfbp5的早熟诱导，这意味着通过抑制Wnt信号而加速退缩过程。肿瘤消退和乳腺退化之间的分子和表型平行表明，WNT驱动的乳腺肿瘤使用与正常乳腺增殖相同的生长机制。癌症资源；72(6)；1568-78年。(C)2012年AACR。
Wnt ligand-driven tumor growth is inhibited by the soluble Wnt inhibitor Fzd8CRD, but the mechanism through which this effect is mediated is unknown. In the MMTV-Wnt1 mouse model, regression of mammary tumors by Fzd8CRD treatment coincides with an acute and strong induction of insulin-like growth factor (IGF)-binding protein IGFBP5, an antagonist of IGF signaling that mediates involution of mammary gland in females after offspring are weaned, In this study, we show that repression of this IGF inhibitory pathway is crucial for Wnt-driven growth of mammary tumors. We found that IGFBP5 regulation was mediated by the beta-catenin-dependent Wnt pathway. Wnt, in addition to IGF ligands, facilitated tumor growth by paracrine communication among tumor cells. In addition, Fzd8CRD caused precocious induction of IGFBP5 in normal mammary glands undergoing involution, implying an acceleration of the involution process by inhibition of Wnt signaling. The molecular and phenotypic parallel between tumor regression and mammary gland involution suggests that Wnt-driven mammary tumors use the same growth mechanism as proliferating normal mammary glands. Cancer Res; 72(6); 1568-78. (C)2012 AACR.