Georgia Cancer Center, Augusta University, Augusta, Georgia.
Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.
Am J Pathol. 2019 Dec;189(12):2450-2458. doi: 10.1016/j.ajpath.2019.08.012. Epub 2019 Sep 19.
The WASF3 gene has been implicated in cancer cell movement, invasion, and metastasis by regulating genetic pathways important in these processes. Invasion and metastasis assays, however, are largely centered on xenograft models in immune-compromised mice. To facilitate analysis of the role of WASF3 in the spontaneous development of cancer cell metastasis, we generated a Wasf3 null strain by deleting exons 4 and 5, which encode essential motifs for Wasf3 function. On exposure to cre-recombinase a stop codon is generated immediately downstream in exon 6. Using a cytomegalovirus (CMV)-cre strain, Wasf3 constitutively was inactivated, which led to viable mice with no visible morphologic or behavioral abnormalities. There was no abnormal development or function of the mouse mammary gland in the Wasf3 null mice and brain development was normal. In the mouse mammary tumor virus (MMTV)-driven polyoma middle-T oncogene strain, which shows early onset breast cancer development and metastasis, Wiskott-Aldrich syndrome protein family member 3 (Wasf3) is up-regulated in metastatic lesions. When this oncogene was introduced onto the Wasf3-null background, although metastasis was observed in these mice, there was a reduction in the number and size of metastatic lesions in the lungs. These data provide evidence for a role in WASF3 in the development of metastasis in a spontaneous model of breast cancer.
WASF3 基因通过调节在这些过程中起重要作用的遗传途径，参与癌细胞的运动、侵袭和转移。然而，侵袭和转移测定主要集中在免疫功能低下的小鼠的异种移植模型上。为了促进分析 WASF3 在癌症细胞转移的自发发展中的作用，我们通过删除编码 WASF3 功能必需基序的外显子 4 和 5 生成了一个 Wasf3 缺失株。在暴露于 cre 重组酶时，外显子 6 下游立即产生一个终止密码子。使用巨细胞病毒 (CMV)-cre 株，WASF3 被持续失活，导致没有明显形态或行为异常的存活小鼠。在 Wasf3 缺失小鼠中，乳腺的发育和功能没有异常，大脑发育正常。在早发性乳腺癌发展和转移的鼠乳腺肿瘤病毒 (MMTV)-驱动的多瘤病毒中间 T 癌基因株中，Wiskott-Aldrich 综合征蛋白家族成员 3 (WASF3) 在转移病变中上调。当这个致癌基因被引入 Wasf3 缺失背景时，尽管这些小鼠观察到转移，但肺部转移病变的数量和大小减少。这些数据为 WASF3 在乳腺癌自发模型中转移的发展中起作用提供了证据。
