IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors.
IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors.
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DOI：
10.1158/0008-5472.can-14-0970
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Wood TL
中科院分区：
文献类型：
--
作者：
Rota LM;Albanito L;Shin ME;Goyeneche CL;Shushanov S;Gallagher EJ;LeRoith D;Lazzarino DA;Wood TL
三阴性乳腺癌（TNBC）是一种侵袭性疾病亚型，与其他亚型不同，缺乏有效的靶向治疗。胰岛素样生长因子受体（IGF-1 R）的抑制剂已被考虑用于治疗TNBC。在这里，我们提供了遗传学证据，证明IGF-1 R抑制会促进Wnt 1介导的小鼠乳腺肿瘤的发展，从而提供了TNBC模型。我们发现，在携带激活的Wnt-1和突变的IGF-1 R的双转基因小鼠模型中，IGF-1 R信号的减少了肿瘤的潜伏期，并促进了更具侵袭性的表型。这些肿瘤表现为鳞状细胞表型，角蛋白5/6和β-连环蛋白表达增加。值得注意的是，细胞谱系分析揭示了基底（CD 29 hi/CD 24+）和管腔（CD 24 +/CD 61 +/CD 29 lo）祖细胞群的增加，沿着Nanog表达增加和Elf 5表达减少。在这些双转基因小鼠中，与MMTV-Wnt 1小鼠不同，肺转移具有原发性肿瘤的特征。机制研究表明，体外IGF-1 R的药理学抑制足以增加MMTV-Wnt 1肿瘤细胞的肿瘤球形成效率。来自双转基因小鼠的肿瘤也表现出IGF-II敏感性胰岛素受体A亚型与IR-B亚型的表达比率增加，这在体外导致β-连环蛋白表达增强。总的来说，我们的研究结果表明，在Wnt驱动的肿瘤中，IGF-1 R信号的减弱加速了肿瘤的发生，并促进了更具侵袭性的表型，这对理解TNBC病理生物学和治疗具有潜在的意义。
Triple-negative breast cancers (TNBC) are an aggressive disease subtype which unlike other subtypes lack an effective targeted therapy. Inhibitors of the insullin-like growth factor receptor (IGF-1R) have been considered for use in treating TNBC. Here we provide genetic evidence that IGF-1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt-1 and mutant IGF-1R, a reduction in IGF-1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamal cell phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29hi/CD24+) and luminal (CD24+/CD61+/CD29lo) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacological inhibition of the IGF-1R in vitro was sufficient to increase the tumorsphere-forming efficiency of MMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor vs the IR-B isoform, which in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors an attenuation of IGF-1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes, with potential implications for understanding TNBC pathobiology and treatment.