Loss of Fbxw7 impairs development of and induces heterogeneous tumor formation in the mouse mammary gland
Loss of Fbxw7 impairs development of and induces heterogeneous tumor formation in the mouse mammary gland
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Fbxw7 的缺失会损害小鼠乳腺的发育并诱导异质性肿瘤的形成
DOI：
10.1158/0008-5472.can-20-0271
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发表时间：
2020
期刊：
影响因子：
11.2
通讯作者：
Nakayama Keiichi I.
中科院分区：
文献类型：
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作者：
Onoyama Ichiro;Nakayama Shogo;Shimizu Hideyuki;Nakayama Keiichi I.
Fbxw7是一种F-box蛋白，在多种组织中参与调节细胞增殖、决定细胞命运以及抑制肿瘤生长。在这项研究中，我们产生了乳腺特异的Fbxw7消融小鼠(BLG-CRE/Fbxw7F/F小鼠)，并发现大多数突变母体所生的新生儿出生后不久就会死亡，这是由于母亲哺乳缺陷造成的。突变鸭乳腺明显萎缩，表现为细胞过度增殖和细胞凋亡，并伴有Notch1和p63的积聚。尽管突变的乳腺具有发育不良的性质，BLG-Cre/Fbxw7F/F小鼠自发地患上了类似于基底细胞样癌的乳腺肿瘤，并具有明显的肿瘤内异质性。在Blg-Cre/Fbxw7F/F小鼠中Trp53的额外失活进一步促进了乳腺肿瘤的发生和发展，这表明Trp53的自发突变可能促进了缺乏Fbxw7的小鼠乳腺发育不良病变向侵袭性癌症的转变。对来自Blg-Cre/Fbxw7F/F小鼠肿瘤的上皮样和间充质样细胞系进行的RNA测序分析显示，肿瘤中的突变率和结构变化增加，以及上游转录因子的差异表达，包括Fbxw7的已知靶点。总之，我们的结果表明Fbxw7参与了乳腺细胞分化的调节和肿瘤的抑制。Fbxw7的缺失增加了突变率和染色体的不稳定性，激活了由Fbxw7调控的转录因子控制的信号通路，并触发了具有显著异质性的乳腺肿瘤的发展。意义：在小鼠乳腺特异性切除Fbxw7会导致腺体发育缺陷和自发的乳腺肿瘤形成，使人想起具有肿瘤内异质性的人类基底样癌。
Fbxw7 is an F-box protein that contributes to regulation of cell proliferation and cell fate determination as well as to tumor suppression in various tissues. In this study, we generated mice with mammary gland–specific ablation of Fbxw7 (Blg-Cre/Fbxw7F/Fmice) and found that most neonates born to mutant dams die soon after birth as a result of defective maternal lactation. The mammary gland of mutant dams was markedly atrophic and manifested both excessive cell proliferation and apoptosis in association with the accumulation of Notch1 and p63. Despite the hypoplastic nature of the mutant mammary gland,Blg-Cre/Fbxw7F/Fmice spontaneously developed mammary tumors that resembled basal-like carcinoma with marked intratumoral heterogeneity. Additional inactivation ofTrp53inBlg-Cre/Fbxw7F/Fmice further promoted onset and development of mammary tumors, suggesting that spontaneous mutation ofTrp53may facilitate transition of hypoplastic mammary lesions to aggressive cancer in mice lacking Fbxw7. RNA-sequencing analysis of epithelial- and mesenchymal-like cell lines from aBlg-Cre/Fbxw7F/Fmouse tumor revealed an increased mutation rate and structural alterations in the tumor and differential expression of upstream transcription factors including known targets of Fbxw7. Together, our results implicate Fbxw7 in the regulation of cell differentiation and in tumor suppression in the mammary gland. Loss of Fbxw7 increases mutation rate and chromosome instability, activates signaling pathways governed by transcription factors regulated by Fbxw7, and triggers the development of mammary tumors with prominent heterogeneity.SignificanceMammary gland–specific ablation of Fbxw7 in mice results in defective gland development and spontaneous mammary tumor formation reminiscent of human basal-like carcinoma with intratumoral heterogeneity.