Wang Zeran, Liu Yueyong, Zhang Pengju, Zhang Weiguo, Wang Weijing, Curr Kenneth, Wei Guangwei, Mao Jian-Hua
Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA, USA.
Oncotarget. 2013 Dec;4(12):2476-86. doi: 10.18632/oncotarget.1581.
Amplification of chromosome 20q is frequently found in various types of human cancers, including breast cancer. The list of candidate oncogenes in 20q has expanded over the past decade. Here, we investigate whether FAM83D (family with sequence similarity 83, member D) on chromosome 20q plays any role in breast cancer development. The expression level of FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers. High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients. We show that ectopic expression of FAM83D in human mammary epithelial cells promotes cell proliferation, migration and invasion along with epithelial-mesenchymal transition (EMT). Ablation of FAM83D in breast cancer cells induces apoptosis and consequently inhibits cell proliferation and colony formation. Mechanistic studies reveal that overexpression of FAM83D downregulates FBXW7 expression levels through a physical interaction, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as mTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion. The results demonstrate that FAM83D has prognostic value for breast cancer patients and is a novel oncogene in breast cancer development that at least in part acts through mTOR hyper-activation by inhibiting FBXW7.
20号染色体长臂扩增在包括乳腺癌在内的多种人类癌症中经常被发现。在过去十年里，20q上的候选致癌基因列表不断扩大。在此，我们研究20号染色体长臂上的FAM83D（序列相似性家族83成员D）在乳腺癌发展中是否发挥任何作用。FAM83D在乳腺癌细胞系和原发性人类乳腺癌中的表达水平显著升高。FAM83D的高表达水平与乳腺癌患者的不良临床结局和远处转移显著相关。我们发现，FAM83D在人乳腺上皮细胞中的异位表达促进细胞增殖、迁移和侵袭，同时伴有上皮-间质转化（EMT）。在乳腺癌细胞中敲除FAM83D可诱导细胞凋亡，从而抑制细胞增殖和集落形成。机制研究表明，FAM83D的过表达通过物理相互作用下调FBXW7的表达水平，这导致FBXW7下游致癌底物的蛋白水平升高，如mTOR，雷帕霉素对其抑制可抑制FAM83D诱导的细胞迁移和侵袭。结果表明，FAM83D对乳腺癌患者具有预后价值，是乳腺癌发展中的一个新致癌基因，至少部分通过抑制FBXW7使mTOR过度激活发挥作用。
